Compounds for treatment of cancer

ABSTRACT

The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-In-Part application of U.S.application Ser. No. 13/216,927, filed Aug. 24, 2011, which is aContinuation-In-Part application of U.S. application Ser. No.12/981,233, filed Dec. 29, 2010 which claims priority from U.S.Provisional Application Ser. No. 61/376,675, filed Aug. 24, 2010; U.S.Provisional Application Ser. No. 61/315,790, filed Mar. 19, 2010; andfrom U.S. Provisional Application Ser. No. 61/309,360, filed Mar. 1,2010; all of which are hereby incorporated by reference in theirentirety.

GOVERNMENT INTEREST STATEMENT

This invention was made in whole or in part with government supportunder Grant Number 1R15CA125623-01A2 and 1R01CA148706-01A1, awarded bythe (National Institutes of Health). The government has certain rightsin the invention.

FIELD OF THE INVENTION

The present invention relates to novel compounds having anti-canceractivity, methods of making these compounds, and their use for treatingcancer, treating drug-resistant tumors, drug-resistant cancer,metastatic cancer, metastatic melanoma, drug resistant melanoma,prostate cancer and drug resistant prostate cancer.

BACKGROUND OF THE INVENTION

Cancer is the second most common cause of death in the United States,exceeded only by heart disease. In the United States, cancer accountsfor 1 of every 4 deaths. The 5-year relative survival rate for allcancer patients diagnosed in 1996-2003 is 66%, up from 50% in 1975-1977(Cancer Facts & Figures American Cancer Society: Atlanta, Ga. (2008)).This improvement in survival reflects progress in diagnosing at anearlier stage and improvements in treatment. Discovering highlyeffective anticancer agents with low toxicity is a primary goal ofcancer research.

Microtubules are cytoskeletal filaments consisting of αβ-tubulinheterodimers and are involved in a wide range of cellular functions,including shape maintenance, vesicle transport, cell motility, anddivision. Tubulin is the major structural component of the microtubulesand a well verified target for a variety of highly successfulanti-cancer drugs. Compounds that are able to interfere withmicrotubule-tubulin equilibrium in cells are effective in the treatmentof cancers. Anticancer drugs like taxol and vinblastine that are able tointerfere with microtubule-tubulin equilibrium in cells are extensivelyused in cancer chemotherapy. There are three major classes ofantimitotic agents. Microtubule-stabilizing agents, which bind to fullyformed microtubules and prevent the depolymerization of tubulinsubunits, are represented by taxanes and epothilones. The other twoclasses of agents are microtubule-destabilizing agents, which bind totubulin dimers and inhibit their polymerization into microtubules. Vinaalkaloids such as vinblastine bind to the vinca site and represent oneof these classes. Colchicine and colchicine-site binders interact at adistinct site on tubulin and define the third class of antimitoticagents.

Both the taxanes and vinca alkaloids are widely used to treat humancancers, while no colchicine-site binders are currently approved forcancer chemotherapy yet. However, colchicine binding agents likecombretastatin A-4 (CA-4) and ABT-751 (FIG. 19), are now under clinicalinvestigation as potential new chemotherapeutic agents (Luo, Y.; Hradil,V. P.; Frost, D. J.; Rosenberg, S. H.; Gordon, G. B.; Morgan, S. J.;Gagne, G. D.; Cox, B. F.; Tahir, S. K.; Fox, G. B., ABT-751, “A noveltubulin-binding agent, decreases tumor perfusion and disrupts tumorvasculature”. Anticancer Drugs 2009, 20(6), 483-92.; Mauer, A. M.;Cohen, E. E.; Ma, P. C.; Kozloff, M. F.; Schwartzberg, L.; Coates, A.I.; Qian, J.; Hagey, A. E.; Gordon, G. B., “A phase II study of ABT-751in patients with advanced non-small cell lung cancer”. J Thorac Oncol2008, 3(6), 631-6.; Rustin, G. J.; Shreeves, G.; Nathan, P. D.; Gaya,A.; Ganesan, T. S.; Wang, D.; Boxall, J.; Poupard, L.; Chaplin, D. J.;Stratford, M. R.; Balkissoon, J.; Zweifel, M., “A Phase Ib trial of CA4P(combretastatin A-4 phosphate), carboplatin, and paclitaxel in patientswith advanced cancer”. Br J Cancer 2010, 102(9), 1355-60.).

Unfortunately, microtubule-interacting anticancer drugs in clinical useshare two major problems, resistance and neurotoxicity. A commonmechanism of multidrug resistance (MDR), namely ATP binding cassette(ABC) transporter protein-mediated drug efflux, limits their efficacy(Green, H.; Rosenberg, P.; Soderkvist, P.; Horvath, G.; Peterson, C.,“beta-Tubulin mutations in ovarian cancer using single strandconformation analysis-risk of false positive results from paraffinembedded tissues”. Cancer Letters 2006, 236(1), 148-54.; Wang, Y.;Cabral, F., “Paclitaxel resistance in cells with reduced beta-tubulin”.Biochimica et Biophysica Acta, Molecular Cell Research 2005, 1744(2),245-255.; Leslie, E. M.; Deeley, R. G.; Cole, S. P. C., “Multidrugresistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP(ABCG2) in tissue defense”. Toxicology and Applied Pharmacology 2005,204(3), 216-237.).

P-glycoproteins (P-gp, encoded by the MDR1 gene) are important membersof the ABC superfamily. P-gp prevents the intracellular accumulation ofmany cancer drugs by increasing their efflux out of cancer cells, aswell as contributing to hepatic, renal, or intestinal clearancepathways. Attempts to co-administer P-gp modulators or inhibitors toincrease cellular availability by blocking the actions of P-gp have metwith limited success (Gottesman, M. M.; Pastan, I., “The multidrugtransporter, a double-edged sword”. J Biol Chem 1988, 263(25), 12163-6.;Fisher, G. A.; Sikic, B. I., “Clinical studies with modulators ofmultidrug resistance”. Hematology/Oncology Clinics of North America1995, 9(2), 363-82).

The other major problem with taxanes, as with many biologically activenatural products, is its lipophilicity and lack of solubility in aqueoussystems. This leads to the use of emulsifiers like Cremophor EL andTween 80 in clinical preparations. A number of biologic effects relatedto these drug formulation vehicles have been described, including acutehypersensitivity reactions and peripheral neuropathies (Hennenfent, K.L.; Govindan, R., “Novel formulations of taxanes: a review. Old wine ina new bottle?” Ann Oncol 2006, 17(5), 735-49.; ten Tije, A. J.; Verweij,J.; Loos, W. J.; Sparreboom, A., “Pharmacological effects of formulationvehicles: implications for cancer chemotherapy”. Clin Pharmacokinet2003, 42(7), 665-85.).

Compared to compounds binding the paclitaxel- or vinca alkaloid bindingsite, colchicine-binding agents usually exhibit relatively simplestructures. Thus providing a better opportunity for oral bioavailabilityvia structural optimization to improve solubility and pharmacokinetic(PK) parameters. In addition, many of these drugs appear to circumventP-gp-mediated MDR. Therefore, these novel colchicine binding sitetargeted compounds hold great promise as therapeutic agents,particularly since they have improved aqueous solubility and overcomeP-gp mediated MDR.

Prostate cancer is one of the most frequently diagnosed noncutaneouscancers among men in the US and is the second most common cause ofcancer deaths with over 180,000 new cases and almost 29,000 deathsexpected this year. Patients with advanced prostate cancer undergoandrogen deprivation therapy (ADT), typically either by luteinizinghormone releasing hormone (LHRH) agonists or by bilateral orchiectomy.Androgen deprivation therapy not only reduces testosterone, but estrogenlevels are also lower since estrogen is derived from the aromatizationof testosterone, which levels are depleted by ADT. Androgen deprivationtherapy-induced estrogen deficiency causes significant side effectswhich include hot flushes, gynecomastia and mastalgia, bone loss,decreases in bone quality and strength, osteoporosis andlife-threatening fractures, adverse lipid changes and highercardiovascular disease and myocardial infarction, and depression andother mood changes.

Leuprolide acetate (Lupron®) is a synthetic nonapeptide analog ofnaturally occurring gonadotropin-releasing hormone (GnRH or LHRH).Leuprolide acetate is an LHRH superagonist that eventually suppresses LHsecretion by the pituitary. Leuprolide acetate acts as a potentinhibitor of gonadotropin secretion, resulting in suppression of ovarianand testicular steroidogenesis. In humans, administration of leuprolideacetate results in an initial increase in circulating levels ofluteinizing hormone (LH) and follicle stimulating hormone (FSH), leadingto a transient increase in levels of the gonadal steroids (testosteroneand dihydrotestosterone in males, and estrone and estradiol inpremenopausal females). However, continuous administration of leuprolideacetate results in decreased levels of LH and FSH. In males,testosterone is reduced to castrate levels (below 50 ng/dL). Inpremenopausal females, estrogens are reduced to postmenopausal levels.Testosterone is a known stimulus for cancerous cells of the prostate.Suppressing testosterone secretion or inhibiting the actions oftestosterone is thus a necessary component of prostate cancer therapy.Leuprolide acetate can be used for LH suppression, which is thereduction and lowering of serum testosterone to castrate levels to treatprostate cancer.

Malignant melanoma is the most dangerous form of skin cancer, accountingfor about 75% of skin cancer deaths. The incidence of melanoma is risingsteadily in Western populations. The number of cases has doubled in thepast 20 years. Around 160,000 new cases of melanoma are diagnosedworldwide each year, and it is more frequent in males and Caucasians.According to a WHO Report, about 48,000 melanoma-related deaths occurworldwide per year.

Currently there is no effective way to treat metastatic melanoma. It ishighly resistant to current chemotherapy, radiotherapy, andimmunotherapy. Metastatic melanoma has a very poor prognosis, with amedian survival rate of 6 months and a 5-year survival rate of less than5%. In the past 30 years, dacarbazine (DTIC) is the only FDA-approveddrug for metastatic melanoma. However, it provides only less than 5% ofcomplete remission in patients. In recent years, great efforts have beenattempted in fighting metastatic melanoma. Neither combinations of DTICwith other chemotherapy drugs (e.g., cisplatin, vinblastine, andcarmustine) nor adding interferon-α2b to DTIC have shown a survivaladvantage over DTIC treatment alone. Most recently, clinical trials withantibodies and vaccines to treat metastatic melanoma also failed todemonstrate satisfactory efficacy. Ipilimumab (Yervoy) is such drug thatuses your immune system to fight melanoma. Ipilimumab is used to treatadvanced melanoma that has spread beyond its original location. Targetedtherapy uses medications designed to target specific vulnerabilities incancer cells. Vemurafenib (Zelboraf) is a targeted therapy approved totreat advanced melanoma that can't be treated with surgery or melanomathat has spread through the body. Vemurafenib only treats melanoma thathas a certain genetic mutation.

Melanoma cells have low levels of spontaneous apoptosis in vivo comparedwith other tumor cell types, and they are relatively resistant todrug-induced apoptosis in vitro. The natural role of melanocytes is toprotect inner organs from UV light, a potent DNA damaging agent.Therefore, it is not surprising that melanoma cells may have special DNAdamage repair systems and enhanced survival properties. Moreover, recentstudies showed that, during melanoma progression, it acquired complexgenetic alterations that led to hyperactivation of efflux pumps,detoxification enzymes, and a multifactorial alteration of survival andapoptotic pathways. All these have been proposed to mediate themultidrug-resistant (MDR) phenotype of melanoma. With the rapidly risingincidence of this disease and the high resistance to current therapeuticagents, developing more effective drugs for advanced melanoma and othercancer types that can effectively circumvent MDR will providesignificant benefits to cancer patients.

SUMMARY OF THE INVENTION

In one embodiment, this invention is directed to a compound of formulaXXIII:

whereinR₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₉ and R₁₂ are independently hydrogen, linear or branched, substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;wherein substitutions are independently selected from the group ofhydroxyl, an aliphatic straight- or branched-chain C₁ to C₁₀hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo,haloalkyl, dihaloalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl,C(O)O-alkyl, C(O)H, C(O)NH₂, —OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl,alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl,urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido,arylamido, aryl, and C₅ to C₇ cycloalkyl, arylalkyl, and combinationsthereof;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;n is an integer between 1-3; andm is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound of formulaXXIV:

whereinR₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₉ and R₁₂ are independently hydrogen, linear or branched, substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;wherein substitutions are independently selected from the group ofhydroxyl, an aliphatic straight- or branched-chain C₁ to C₁₀hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo(e.g., F, Cl, Br, I), haloalkyl, dihaloalkyl, trihaloalkyl, COOH,C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H, C(O)NH₂, —OC(O)CF₃, —OCH₂Ph,amino, aminoalkyl, alkylamino, mesylamino, dialkylamino, arylamino,amido, NHC(O)-alkyl, urea, alkyl-urea, alkylamido (e.g., acetamide),haloalkylamido, arylamido, aryl, and C₅ to C₇ cycloalkyl, arylalkyl, andcombinations thereof;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;n is an integer between 1-3; andm is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound of formulaXXV:

whereinR₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₉ and R₁₂ are independently hydrogen, linear or branched, substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;wherein substitutions are independently selected from the group ofhydroxyl, an aliphatic straight- or branched-chain C₁ to C₁₀hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo,haloalkyl, dihaloalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl,C(O)O-alkyl, C(O)H, C(O)NH₂, —OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl,alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl,urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido,arylamido, aryl, and C₅ to C₇ cycloalkyl, arylalkyl, and combinationsthereof;i is an integer between 0-5;n is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In another embodiment, this invention is directed to the followingcompounds:

-   (4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone (70a);-   (4-(4-fluorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70b);-   (4-(4-chlorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70c);-   (4-(4-bromophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70d);-   (4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70e);-   (4-p-tolyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone (70f);-   (4-(4-methoxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70g);-   (4-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70h);-   (4-(4-hydroxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70i);-   (5-methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70j);-   (5-ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70k);-   (4-phenyl-5-propyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70l);-   (1-methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70m);-   (1-ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70n);-   (1-benzyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70o); or-   (1-cyclopentyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70p).

In another embodiment, the compound of this invention is its isomer,pharmaceutically acceptable salt, pharmaceutical product, tautomer,hydrate, N-oxide, or combinations thereof.

In one embodiment, this invention is directed to a pharmaceuticalcomposition comprising a compound of this invention and apharmaceutically acceptable carrier.

In one embodiment this invention is directed to a method of (a)treating, suppressing, reducing the severity, reducing the risk, orinhibiting cancer; (b) treating a drug resistant tumor or tumors; and(c) destroying a cancerous cell comprising administering a compound ofthis invention. In another embodiment the cancer is selected from thegroup consisting of prostate cancer, breast cancer, ovarian cancer, skincancer, melanoma, lung cancer, colon cancer, leukemia, renal cancer, CNScancer, and combinations thereof. In another embodiment, the cancer ismetastatic cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1 depicts the synthesis of the diverse B-ring template: oxazole.Reagents and conditions: (a) MeOH, CH₃COCl, 83%; (b) Benzimidic acidethyl ester, CH₂Cl₂, Et₃N, 96%; (c) LiOH, MeOH, H₂O, 65%; (d) EDCI,HOBt, NMM, CH₃OCH₃NH.HCl, 61%; (e) 3,4,5-trimethoxyphenylmagnesiumbromide, THF, 48%-71%; (f) CBrCl₃, DBU, CH₂Cl₂, 56%.

FIG. 2 depicts the synthesis of the diverse B-ring templates. Reagentsand conditions: (a) EDCI, HOBt, NMM, CH₃OCH₃NH.HCl, CH₂Cl₂, 51-95%; (b)3,4,5-trimethoxyphenyl-magnesium bromide, THF, 48-78%; (c) LAH, −78° C.,THF, 85%; (d) Dess-Martin reagent, CH₂Cl₂, 81%; (e) EDCI, HOBt, NMM,3,4,5-trimethoxybenzoic acid, CH₂Cl₂, 58%.

FIG. 3 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) MeOH/pH=6.4 phosphate buffer, RT; (b) EDCI,HOBt, NMM, HNCH₃OCH₃; (c) CBrCl₃, DBU, CH₂Cl₂; (d)3,4,5-trimethoxyphenylmagnesium bromide, THF; (e) isopropyltriphenylphosphonium iodide, n-BuLi, THF; (f) LAH, THF; (g) For 2e-cisand 2e-trans, NH₂OH.HCl, C₂H₅OH, H₂O, NaOH; For 2g and 2h, NH₂OMe.HCl,pyridine; (h) TsCl, NaH, basic Al₂O₃; (i) NH₂NH₂.xH₂O, CH₂Cl₂, t-BuOH;(j) diethyl cyanomethylphosphonate, n-BuLi, THF; (k)bis-trimethylsilylcarbodiimide, TiCl₄, CH₂Cl₂; (l) EDCI, HOBt, Et₃N,3,4,5-trimethoxyaniline, CH₂Cl₂.

FIG. 4 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) bromine, EtOH; (b) benzothioamide, EtOH,reflux; (c) EDCI, HOBt, NMM, HNCH₃OCH₃, CH₂Cl₂; (d) CBrCl₃, DBU, CH₂Cl₂;(e) LAH, THF; (f) 5-(bromomethyl)-1,2,3-trimethoxybenzene, Ph₃P, THF;(g) n-BuLi, THF; (h) (1) HCl, H₂O; (2) NaNO₂, H₂O, 0° C.; (i) ethylpotassium xanthate; (j) KOH/EtOH; (k) H₂O, HCl; (l)5-iodo-1,2,3-trimethoxybenzene, Cut t-BuONa; (m) 2 equiv or 1 equivm-CPBA, CH₂Cl₂; (n) 3,4,5-trimethoxyaniline, NEt₃, DMF.

FIG. 5 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) L-cysteine, EtOH, 65° C.; (b) EDCI, HOBt,NMM, HNCH₃OCH₃, CH₂Cl₂; (c) TBDMSCl, imidazole, THF; (d)3,4,5-trimethoxyphenylbromide, BuLi, THF; (e) TBAF, THF; (f) SOCl₂,Et₂O; (g) NH₃, MeOH; (h) POCl₃; (i) PhSO₂Cl, Bu₄NHSO₄, toluene, 50%NaOH; (j) 1 N NaOH, EtOH, reflux; (k) Boc₂₀, 1 N NaOH, 1,4-dioxane; (l)CBrCl₃, DBU, CH₂Cl₂; (m) 4 N HCl in 1,4-dioxane; (n) NaH, DMF, MeI;(o)HCHO, NaBH₃CN, Et₃N.

FIG. 6 depicts the synthetic scheme of compounds of this invention.Reagents and conditions: (a) EtOH, 65° C.; (b) NaOH, C₂H₅OH, refluxing;(c) EDCI, HOBt, NMM, HNCH₃OCH₃, CH₂Cl₂; (d)3,4,5-trimethoxyphenylbromide, BuLi, THF; (e) 2 N HCl in 1,4-dioxane.

FIG. 7 depicts a synthetic scheme for the preparation ofAryl-Benzoyl-Imidazole (ABI) compounds of this invention. Reagents andconditions: (a) t-BuOH, I₂, ethylenediamine, K₂CO₃, reflux; (b) PhI(OAc)₂, K₂CO₃, DMSO; (c) DBU, CBrCl₃, DMF; (d) NaH, PhSO₂Cl, THF, 0°C.-RT; (e) t-BuLi, substituted benzoyl chloride, THF, −78° C.; (f)Bu₄NF, THF, RT.

FIG. 8 depicts a synthetic scheme for the preparation ofAryl-Benzoyl-Imidazole (ABI) compounds of this invention. Reagents andconditions: (a) NH₄OH, oxalaldehyde, ethanol, RT; (b) NaH, PhSO₂Cl, THF,0° C.-RT; (c) t-BuLi, substituted benzoyl chloride, THF, −78° C.; (d)Bu₄NF, THF, RT; (e) BBr₃, CH₂Cl₂; (f) c-HCl, AcOH, reflux.

FIG. 9 depicts a synthetic scheme for the preparation ofAryl-Benzoyl-Imidazole (ABI) compounds of this invention. Reagents andconditions: (a) NaH, substituted benzoyl chloride, THF.

FIG. 10 depicts the synthetic scheme of compounds 12dc, 12fc, 12daa,12dab, 12cba. (a) AlCl₃, THF, reflux; (b) NaH, CH₃I for 12dab and 12cbaand BnBr for 12daa, THF, reflux.

FIG. 11 depicts the synthetic scheme of compounds 11gaa, 12la. (a)NH₄OH, ethanol, glyoxal, RT; (b) NaH, substituted PhSO₂Cl, THF, 0°C.-RT; (c) t-BuLi (1.7 M in pentane), substituted benzoyl chloride, THF,−78° C.; (d) Bu₄NF, RT.

FIG. 12 depicts the synthetic scheme of compound 15xaa and 12xa. (a) 1.KOH, ethanol; 2. PhSO₂Cl, acetone, RT; (b) NH₄OH, glyoxal, ethanol, RT;(c) NaH, PhSO₂Cl, THF, 0° C.-RT; (d) t-BuLi (1.7 M in pentane),3,4,5-trimethoxybenzoyl chloride, THF, −78° C.; (e) NaOH, ethanol, H₂O,reflux.

FIG. 13 depicts synthetic scheme of 17ya, 17yab and 17yac. (a) 1. KOH,ethanol, 2. PhSO₂Cl, acetone, RT; (b) NH₄OH, glyoxal, ethanol, RT; (c)NaH, PhSO₂Cl, THF, 0° C.-RT; (d) t-BuLi (1.7 M in pentane),3,4,5-trimethoxybenzoyl chloride, THF, −78° C.; (e) NaOH, ethanol, H₂O,reflux; (f) TBAF, THF, RT; (g) NaH, CH₃I, THF.

FIG. 14 depicts synthetic scheme of 12fa. (a) NH₄OH, oxalaldehyde,ethanol, RT; (b) NaH, PhSO₂Cl, THF, 0° C.-RT; (c) t-BuLi,3,4,5-trimethoxybenzoyl chloride, THF, −78° C.; (d) Bu₄NF, THF, RT.

FIG. 15 depicts a synthetic scheme of compound 55.

FIG. 16 depicts a synthetic scheme of isoquinoline and quinoline basedcompounds. FIG. 16A depicts the synthetic scheme of isoquinolinederivatives. Reagents and conditions: a) arylboronic acid (1 equiv.),Pd(PPh₃)₄ (0.01 equiv.), K₂CO₃, H₂O, DMF, 5 h; b) arylboronic acid (2.4equiv.), Pd(PPh₃)₄ (0.04 equiv.), K₂CO₃, H₂O, DMF, 16 h; c) arylboronicacid (1.2 equiv.), Pd(PPh₃)₄ (0.04 equiv.), K₂CO₃, H₂O, DMF, 16 h. FIG.16B depicts the synthetic scheme of compounds 41 and 44. Reagents andconditions: a) p-fluorobenzenesulfonyl chloride, pyridine, pyridine, 80°C., 3 h; b) 5-indoleboronic acid (1.2 equiv.), Pd(PPh₃)₄ (0.02 equiv.),K₂CO₃, H₂O, DMF, 16 h. FIG. 16C depicts the synthetic scheme ofisoquinoline derivative 6d. FIG. 16D depicts the synthetic scheme ofisoquinoline derivative 6c. FIG. 16E depicts the synthetic scheme ofisoquinoline derivative 6b.

FIG. 17 depicts a standard solubility curve for ABI compound 12ga(dissolved in acetonitrile). X-axis is the amount of compound and y-axisis the m/z peak area.

FIG. 18 depicts the measured aqueous solubility for anti-tubulincompounds 1h, 1c, 66a, 2r-HCl, 5a, and 5c.

FIG. 19 depicts the structures of colchicine-binding site tubulininhibitors.

FIG. 20 depicts the ability of anti-tubulin compounds 1h, 1c, 2j, 66aand 5a to inhibit tubulin polymerization in vitro (FIG. 20 a) and 5c(FIG. 20 b), and the 5Hc binding to colchicine site (FIG. 20 c).

FIG. 21 depicts dose-response curves of 2-aryl-4-benzoyl-imidazolecompounds (ABIs) compared with other anticancer drugs and compounds onmultidrug resistant melanoma cell line (MDR cell) and the matchedsensitive parent cell line (Normal Melanoma cell). The large distancebetween the two curves for paclitaxel, vinblastine, and colchicineindicates that they were substrates for P-glycoprotein (P-gp). Theoverlapping two curves of each ABI compound indicate that the ABIcompounds were not substrates for P-gp and overcame multidrugresistance.

FIG. 22 presents the effect of ABI compounds on tubulin polymerizationin vitro. Tubulin (0.4 mg/assay) was exposed to 10 μM ABI compounds(vehicle control, 5% DMSO). Absorbance at 340 nm was monitored at 37° C.every minute for 15 min and demonstrated that ABI compounds 12da, 12db,and 12cb inhibited tubulin polymerization in vitro.

FIG. 23 depicts B16-F1 melanoma colony formation assay in soft agarwhich showed that ABI compounds inhibited colony formation in aconcentration-dependent manner. FIG. 23A depicts representative picturesof control and each tested compound (12cb, 12da, and 12fb) at 100 nM.The diameter of each well was 35 mm. FIG. 23B depicts a quantifiedrepresentation of assay results for each tested compound (12cb, 12da,and 12fb). P value was calculated comparing with control using Student'st test by GraphPad Prism software. Columns, means of three replicates;bars, SD.

FIG. 24 depicts in vivo study of ABI compounds. FIG. 24A depicts the invivo activity of 12cb against B16-F1 melanoma tumors in C57/BL mice.FIG. 24B depicts the in vivo activity of 12fb against B16-F1 melanoma inC57BL/6 mice and SHO nude mice. Results showed that 12fb inhibitedmelanoma tumor growth in a dose-dependent manner. C57BL/6 mice bearingB16-F1 melanoma allograft (n=5 per group). Each mouse received 0.5×10⁶cells by s.c. injection into the flank. 30 μL i.p. daily treatments werestarted when tumor size reached ˜100 mm³. FIG. 24C depicts the in vivoactivity of 12fb against an A375 human melanoma xenograft. SHO nude micebearing an A375 human melanoma xenograft (n=5 per group). Each mousereceived 2.5×10⁶ cells by s.c. injection into the flank. 30 μL i.p.daily treatments were started when the tumor size reached ˜150 mm³.Control, vehicle solution only; points, means; bars, SD. DTIC,(5-(3,3,-dimethyl-1-triazenyl)-imidazole-4-carboxamide, dacarbazine.

FIG. 25 depicts a competitive colchicine binding assay. FIG. 25A depictsa [³H]-colchicine competition-binding scintillation proximity assaywhich showed that 12cb competitively bound to tubulin colchicine bindingsite. FIG. 25B depicts representative graphs of cell cycle analysisusing flow cytometry which showed that ABI compounds (examples shown for12da and 12fb) arrested A375 cells in the G2/M phase after 24 hincubation. The effect and potency were similar to those of colchicine.FIG. 25C shows quantified graphic depictions of cell cycle analysis. Alltested compounds (examples shown for 12cb, 12da, and 12fb) arrested A375cells in the G2/M phase in a dose-dependent manner. ABI 12da showedgreater potency than did colchicine. FIG. 25D depicts a cell cycleanalysis using flow cytometry of A375 cells after being incubated with12cb, 12da, and 12fb at different concentrations for 24 h. Colchicinearrested most cells in the G2/M phase starting from 50 nM. 12cb, 12da,and 12fb also arrested most cells in the G2/M phase starting from 200,50, and 200 nM respectively.

FIG. 26 depicts the effect of 17ya and 55 on tubulin polymerization.Compounds 17ya and 55 bind to colchicine-binding site on tubulin, andinhibit tubulin polymerization. FIG. 26A, competitive mass binding.Tubulin (1 mg/mL) and colchicine (1.2 μM) were incubated with variousconcentrations of podophylltoxin, vinblastine, compounds 17ya, and 55.N=3; mean±SD. Podophylltoxin and vinblastine were used as positive andnegative controls, respectively. FIG. 26B, effect on tubulinpolymerization. Tubulin (0.4 mg) was exposed to test compounds (5 μM).Colchicine was used as positive control. FIGS. 26C and 26D, ability of17ya and 55 to enhance cytoplasmic DNA-Histone complex formation(apoptosis) at 24 h in PC-3 (C) and PC-3/TxR (D) cells (N=3); mean±SD.Docetaxel was used as positive control.

FIG. 27 depicts in vivo anticancer efficacy. FIG. 27A, Nude mice bearingPC-3 tumors were treated with docetaxel (i.v., 10 or 20 mg/kg) on day 1and 9. (N=5-6). Bars, SE. FIG. 27B, Nude mice bearing PC-3/TxR tumorswere treated with docetaxel (i.v., 10 or 20 mg/kg) on day 1 and 9,compound 17ya treatments (p.o., 6.7 mg/kg) once daily, five days a week.(N=4-5). Bars, SE. FIG. 27C, Nude mice bearing PC-3/TxR tumors weretreated with compound 17ya (PO, 3.3 mg/kg) twice a day for four days inthe first week, and then dosed once a day, five days a week for weeks2-4 (N=7), with compound 55 treatments (p.o., 10 or 30 mg/kg) twice aday, five days a week for four weeks (N=7). Bars, SE. FIG. 27D, Nudemice bearing PC-3/TxR tumors were treated with compound 17ya (PO, 10mg/kg) three times a week for four weeks (N=5). Bars, SE.

FIG. 28 depicts that compounds 1h, 2k, and 2l inhibit tubulinpolymerization via binding to the colchicine binding site on tubulin.(FIG. 28A) Structures of 1h (—H), 2k (—F), and 2l (—OH). (FIG. 28B)Effect of the compounds on tubulin polymerization. Tubulin (0.4 mg) wasexposed to compounds 1h, 2k, and 2l (10 μM). Absorbance at 340 nm wasmonitored every min for 15 min. (FIG. 28C) Ability of 1h to compete forcolchicine, vinblastine and paclitaxel binding sites on tubulin usingmass spectrometry competitive binding assay (n=3); bars, SD.

FIG. 29 depicts that compounds 1h, 2k and 2l arrested cells into G2/Mphase and induced apoptosis. (FIG. 29A) Representative graphs of cellcycle analysis after compounds treatment for 24 h on PC-3 and A375cells. (FIG. 29B) The changes in G2/M proportion induced by 1h, 2k, and2l in PC-3 and A375 cells after 24 h treatment. (FIG. 29C) Ability of1h, 2k, and 2l to enhance cytoplasmic DNA-Histone complex formation in24 h (n=3); bars, SD. Colchicine and vinblastine were used as positivecontrols.

FIG. 30 depicts pharmacokinetic studies of 1h, 2k and 2l administeredi.p. in mice and rats. (FIG. 30A) Concentration-time curve of SMARTcompounds in ICR mice (n=3); bars, SD. SMART compounds wereadministrated 15 mg/kg i.v. by tail vein injection. (FIG. 30B)Concentration-time curve of 1h and 2k in SD rats (n=4); bars, SD.Spague-Dawley rats were dosed 2.5 mg/kg i.v. with the formulationDMSO/PEG300 (1/4).

FIG. 31 presents in vivo anti-cancer efficacy (administered i.p.) andneurotoxicity of SMART compounds in mice. (FIG. 31A) SMART compoundsefficacy for PC-3 prostate tumor xenografted on nude mice (n=6-8). (FIG.31B) Vinblastine efficacy for PC-3 prostate tumor xenografted on nudemice (n=8). This served as the positive control. (FIG. 31C) In vivoefficacy of 1h and 2k in nude mice bearing A375 melanoma xenografts(n=10). Nude mice were inoculated with 2.5×10⁶ PC-3 or A375 cells anddosed i.p. daily (SMART compounds) and q2d (vinblastine) after tumorformation (150-200 mm³). Each point represents mean tumor volume foranimals in each group. (FIG. 31D) In vivo neurotoxicity (rotarod test)of 1h in ICR mice (n=7 or 8). 1h (5 and 15 mg/kg), vinblastine (0.5mg/kg) and vehicle were given i.p. daily, and vinblastine was used asthe positive control. The dosing was stopped on day 31. *, p<0.05. Bars,SE.

FIG. 32 depicts molecular modeling of ABI compounds that target tubulinin the colchicine binding site. FIGS. 32A and 32B depict molecularmodeling of compound 12cb and 11cb, respectively.

FIG. 33 depicts microscopic images of immunofluorescence-labeledmicrotubules in WM-164 melanoma cells, which showed microtubule modalitywas dramatically changed after compound treatment for 18 h. Thisprovides visual proof that ABI compounds target tubulin and disruptfunctional microtubule formation.

FIG. 34 depicts the efficacy and tolerability of 6b and 6c in xenograftmodels after i.p. injection. FIG. 34A. PC-3 xenografts were treated withvehicle (qd), 6b (40 mg/kg, qd), or 6c (40 mg/kg, qd) for 3 weeks.Dosing vehicles were composed of 20% Captex200 in Tween80. The tumorvolumes (mm³) were plotted against time and are the means±SD from eightanimals. The tumor volumes were shown in left panel and body weightswere shown in right panel. FIG. 34B. The liver size (g) of each nudemouse was measured after 3 weeks treatment. FIG. 34C. The number ofwhite blood cells was counted in whole blood collected from animal after3 weeks treatment.

FIG. 35—Compound 17ya showed potent endothelial cell growth inhibition.Cell growth inhibition of doxorubicin (FIG. 35A) and compound 17ya (FIG.35B) was investigated in several cell lines by SRB study. Thedefinitions HUVEC-active and HUVEC-inactive represent growthfactor-supplemented and growth factor-deprived endothelial cellcultures, respectively.

FIG. 36—Disruption of preformed capillary by 17ya. HUVEC cells loaded onMatrigel were allowed to make tube for 16 h and the test compound wastreated to the preformed tubes. The number of tubes (A, B, and C) andnodes (D, E, and F) were counted up to 25 h after drug treatment. PanelsA and D are conditions in the presence of CA4, panels B and E areconditions in the presence of doxorubicin and panels C and F areconditions in the presence of 17ya.

FIG. 37-Inhibition of the endothelial capillary formation and disruptionof preformed capillaries. Inhibition of capillary formation () anddisruption of preformed capillary (◯) were compared in vitro study usingHUVEC cells after 15 h CA4 (A and D), DOX (B and E), and 17ya (C and F)treatment. Arrow shows the IC₅₀ value of each compound in HUVEC cellgrowth inhibition.

FIGS. 38-17 ya and 55 increased the permeability of endothelial cellmonolayers. Confluent HUVEC monolayers were exposed to test compound.The leakage of FITC-conjugated dextran through the monolayer wasassessed by relative fluorescence measurements at λ=485 nm excitationand λ=530 nm emission in a receiver to determine changes in monolayerpermeability following exposure.

FIG. 39 depicts PC3 cell cycle distribution for 24 hours treatment ofcompounds of this invention (12q, 70a, 70f and 70m)

FIG. 40 depicts a synthetic scheme of aryl benzoyl imidazole compoundsof this invention.

FIG. 41 depicts a synthetic scheme of aryl benzoyl substituted-imidazolecompounds of this invention.

FIG. 42 depicts the in vivo anti-cancer efficacy of 17ya in HL60leukemia cell xenografts.

It will be appreciated that for simplicity and clarity of illustration,elements shown in the figures have not necessarily been drawn to scale.For example, the dimensions of some of the elements may be exaggeratedrelative to other elements for clarity. Further, where consideredappropriate, reference numerals may be repeated among the figures toindicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, this invention is directed to a compound of formula(I)

whereinA and C are each independently substituted or unsubstituted single-,fused- or multiple-ring aryl or (hetero)cyclic ring systems; substitutedor unsubstituted, saturated or unsaturated N-heterocycles; substitutedor unsubstituted, saturated or unsaturated S-heterocycles; substitutedor unsubstituted, saturated or unsaturated O-heterocycles; substitutedor unsubstituted, saturated or unsaturated cyclic hydrocarbons; orsubstituted or unsubstituted, saturated or unsaturated mixedheterocycles;

B is

R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, —C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;wherein said A and C rings are optionally substituted by 1-5substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I,haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 0-5;l in an integer between 1-2;whereinif B is a benzene ring, a thiophene ring, a furan ring or an indole ringthen X is not a bond or CH₂, and A is not indole;if B is indole then X is not O; andor its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula I is a thiazole ring then X is not abond.

In one embodiment, A in compound of Formula I is indolyl. In anotherembodiment A is 2-indolyl. In another embodiment A is phenyl. In anotherembodiment A is pyridyl. In another embodiment A is naphthyl. In anotherembodiment A is isoquinoline. In another embodiment, C in compound ofFormula I is indolyl. In another embodiment C is 2-indolyl. In anotherembodiment C is 5-indolyl. In another embodiment, B in compound ofFormula I is thiazole. In another embodiment, B in compound of Formula Iis thiazole; Y is CO and X is a bond. Non limiting examples of compoundof formula I are selected from:(2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8) and(2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone (21).

In one embodiment, this invention is directed to a compound of formula(Ia)

whereinA is substituted or unsubstituted single-, fused- or multiple-ring, arylor (hetero)cyclic ring systems; substituted or unsubstituted, saturatedor unsaturated N-heterocycles; substituted or unsubstituted, saturatedor unsaturated S-heterocycles; substituted or unsubstituted, saturatedor unsaturated O-heterocycles; substituted or unsubstituted, saturatedor unsaturated cyclic hydrocarbons; or substituted or unsubstituted,saturated or unsaturated mixed heterocycles;

B is

R₁, R₂ and R₃ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, —C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;wherein said A ring is optionally substituted by 1-5 substituents whichare independently O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃,CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branched alkyl, haloalkyl,alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph,C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 0-5;l is an integer between 1-2;m is an integer between 1-3;whereinif B is a benzene ring, a thiophene ring, a furan ring or an indole ringthen X is not a bond or CH₂ and A is not indole;if B is indole then X is not O;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula Ia is a thiazole ring then X is not abond.

In one embodiment, this invention is directed to a compound of formula(II):

wherein

B is

R₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;l is an integer between 1-2;n is an integer between 1-3; andm is an integer between 1-3;whereinif B is indole then X is not O;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula II is a thiazole ring then X is not abond.

In one embodiment, this invention is directed to a compound of formula(III)

wherein

B is

R₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; andR₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;l is an integer between 1-2; andn is an integer between 1-3;whereinif B is indole then X is not O;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula III is a thiazole ring then X is nota bond.

In one embodiment, this invention is directed to a compound of formula(IV)

wherein ring A is an indolyl;

B is

R₁ and R₂ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;wherein said A is optionally substituted by O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; andi is an integer between 0-5;l is an integer between 1-2; andm is an integer between 1-4;whereinif B is a benzene ring, a thiophene ring, a furan ring or an indole ringthen X is not a bond or CH₂;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula IV is a thiazole ring then X is not abond.

In another embodiment, the indolyl of ring A of formula IV is attachedto one of its 1-7 positions to X or direct to B if X is a bond (i.enothing).

In one embodiment, this invention is directed to a compound of formulaIV(a)

B is

R₁, R₂, R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; andR₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond or C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;l is an integer between 1-2;n is an integer between 1-2; andm is an integer between 1-4;whereinif B is a benzene ring, a thiophene ring, a furan ring or an indole ringthen X is not a bond or CH₂;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, if B of formula IVa is a thiazole ring then X is nota bond.

In one embodiment, this invention is directed to a compound of formula(V)

B is

R₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 1-5;l is an integer between 1-2; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In another embodiment, B of formula V is not a thiazole

In another embodiment, B of formula V is not an oxazole. In anotherembodiment, B of formula V is not an oxazoline. In another embodiment, Bof formula V is not an imidazole. In another embodiment, B of formula Vis not a thiazole, oxazole, oxazoline or imidazole.

In one embodiment, this invention is directed to the followingcompounds:

Formula V

Compound B R₄, R₅ and R₆ 1a

H 1b

H 1c

H 1d

H 1e

H 1f

H 1g

H 1h

H 1i

H 1k

H 1l

H 35a 

H 36a 

H

In one embodiment, this invention is directed to a compound of formula(VI)

whereinR₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; andY is a bond or C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;n is an integer between 1-3; andi is an integer from 1-5;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to the followingcompounds:

Formula VI

Compound Y R₄, R₅ and R₆ 1h —C═O H 2a —C═C(CH₃)₂ H 2b —CH—OH H 2c—C═CH—CN H (cis and trans) 2d —C═N—NH₂ H (cis and trans) 2e —C═N—OH H(cis and trans) 2f —C═N—OMe H (cis and trans) 2g —(C═O)—NH— H 2h—NH—(C═O)— H 2i nothing H 2j —C═N—CN H (cis and trans) 2k C═O R₄ = R₆ =H R₅ = p-F 21 C═O R₄ = R₆ = H R₅ = p-OH 2m C═O R₄ = R₆ = H R₅ = p-CH₃ 2nC═O R₄ = R₆ = H R₅ = p-CH₂—CN 2o C═O R₄ = R₆ = H R₅ = p-N(CH₃)₂ 2p C═OR₄ = m-F; R₅ = p-F; R₆ = m-F; n = 1 2q C═O R₄ = R₆ = H R₅ =p-CH₂—(C═O)NH₂ 2r C═O R₄ = R₆ = H R₅ = p-CH₂NH₂ 2s C═O R₄ = R₆ = H R₅ =p-CH₂NH—CH₃ 2t C═O R₄ = m-OMe; R₅ = p-OMe; R₆ = m-OMe; n = 1 2u C═O R₄ =R₆ = H R₅ = p-CH₂NMe₂

In one embodiment, this invention is directed to compound 3a:

In one embodiment, this invention is directed to compound 3b:

In one embodiment, this invention is directed to a compound of formula(VII)

whereinY is a bond or C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to the followingcompounds:

Formula VII

Compound Y 4a S 4b SO₂ 4c SO 4d —(SO₂)—NH—

In one embodiment, this invention is directed to a compound of formula(VIII)

whereinR₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;

Q is S, O or NH;

i is an integer between 0-5; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to the followingcompounds:

Formula VIII

Compound R₄ R₅ R₆ Q 5a H H H S n = 1 5b H p-CH₃ H S n = 1 5c H p-F H S n= 1 5d H p-Cl H S n = 1 5e H H H N n = 1

In one embodiment, this invention is directed to a compound of formula(IX)

whereinR₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —(O)NH₂ or NO₂;A′ is halogen; substituted or unsubstituted single-, fused- ormultiple-ring, aryl or (hetero)cyclic ring systems; substituted orunsubstituted, saturated or unsaturated N-heterocycles; substituted orunsubstituted, saturated or unsaturated S-heterocycles; substituted orunsubstituted, saturated or unsaturated O-heterocycles; substituted orunsubstituted, saturated or unsaturated cyclic hydrocarbons; orsubstituted or unsubstituted, saturated or unsaturated mixedheterocycles; wherein said A′ ring is optionally substituted by 1-5substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I,haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 1-5; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, a compound of Formula IX is represented by thestructures of the following compounds:

Formula IX

Compound A′ R₄, R₅ 6a

H 6b

H 6c

H 6d Cl H

In another embodiment A′ of formula IX is a halogen. In one embodimentA′ of formula IX is a phenyl. In another embodiment A′ of formula IX issubstituted phenyl. In another embodiment the substitution of A′ ishalogen. In another embodiment the substitution is 4-F. In anotherembodiment the substitution is 3,4,5-(OCH₃)₃. In another embodiment, A′of formula IX is substituted or unsubstituted 5-indolyl. In anotherembodiment, A′ of formula IX is substituted or unsubstituted 2-indolyl.In another embodiment, A′ of formula IX is substituted or unsubstituted3-indolyl. In another embodiment, compounds of formula IX are presentedin FIG. 16A.

In one embodiment, this invention is directed to a compound of formula(IXa)

whereinR₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br,I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)₁NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —(O)NH₂ or NO₂;A′ is halogen; substituted or unsubstituted single-, fused- ormultiple-ring, aryl or (hetero)cyclic ring systems; substituted orunsubstituted, saturated or unsaturated N-heterocycles; substituted orunsubstituted, saturated or unsaturated S-heterocycles; substituted orunsubstituted, saturated or unsaturated O-heterocycles; substituted orunsubstituted, saturated or unsaturated cyclic hydrocarbons; orsubstituted or unsubstituted, saturated or unsaturated mixedheterocycles; wherein said A′ ring is optionally substituted by 1-5substituents which are independently O-alkyl, O-haloalkyl, F, Cl, Br, I,haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer between 1-5; andn is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In another embodiment A′ of formula IXa is a halogen. In one embodimentA′ of formula IXa is a phenyl. In another embodiment A′ of formula IXais substituted phenyl. In another embodiment the substitution of A′ ishalogen. In another embodiment the substitution is 4-F. In anotherembodiment the substitution is 3,4,5-(OCH₃)₃. In another embodiment, A′of formula IXa is substituted or unsubstituted 5-indolyl. In anotherembodiment, A′ of formula IXa is substituted or unsubstituted 2-indolyl.In another embodiment, A′ of formula IXa is substituted or unsubstituted3-indolyl.

In another embodiment, a compound of formula IXa is1-chloro-7-(4-fluorophenyl)isoquinoline. In another embodiment, acompound of formula IXa is7-(4-fluorophenyl)-1-(1H-indol-5-yl)isoquinoline. In another embodiment,a compound of formula IXa is7-(4-fluorophenyl)-1-(3,4,5-trimethoxyphenyl)isoquinoline. In anotherembodiment, a compound of formula IXa is1,7-bis(4-fluorophenyl)isoquinoline (40). In another embodiment, acompound of formula IXa is 1,7-bis(3,4,5-trimethoxyphenyl)isoquinoline.In another embodiment, a compound of formula IXa is1-(4-fluorophenyl)-7-(3,4,5-trimethoxyphenyl)isoquinoline. In anotherembodiment, a compound of formula IXa is1-(1H-indol-5-yl)-7-(3,4,5-trimethoxyphenyl)isoquinoline. In anotherembodiment, a compound of formula IXa is1-chloro-7-(3,4,5-trimethoxyphenyl)isoquinoline.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI:

whereinX is a bond, NH or S;

Q is O, NH or S; and

A is substituted or unsubstituted single-, fused- or multiple-ring arylor (hetero)cyclic ring systems; substituted or unsubstituted, saturatedor unsaturated N-heterocycles; substituted or unsubstituted, saturatedor unsaturated S-heterocycles; substituted or unsubstituted, saturatedor unsaturated O-heterocycles; substituted or unsubstituted, saturatedor unsaturated cyclic hydrocarbons; or substituted or unsubstituted,saturated or unsaturated mixed heterocycles; wherein said A ring isoptionally substituted by 1-5 1-5 substituents which are independentlyO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,C₁-C₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl,—OCH₂Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ orNO₂; andi is an integer from 0-5;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment if Q of Formula XI is S, then X is not a bond.

In one embodiment, A of compound of Formula XI is Ph. In anotherembodiment, A of compound of Formula XI is substituted Ph. In anotherembodiment, the substitution is 4-F. In another embodiment, thesubstitution is 4-Me. In another embodiment, Q of compound of Formula XIis S. In another embodiment, X of compound of Formula XI is NH. Nonlimiting examples of compounds of Formula XI are selected from:(2-(phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5a),(2-(p-tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5b),(2-(p-fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(5c),(2-(4-chlorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(5d),(2-(phenylamino)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(5e), (2-(phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Ha),(2-(p-tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hb),(2-(p-fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hc),(2-(4-chlorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hd),(2-(phenylamino)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5He).

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(a):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(b):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(c):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(d):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound representedby the structure of formula XI(e):

wherein R₄ and R₅ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₉ is H, linear or branched, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;i is an integer from 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In another embodiment, a compound of formula XI is represented by thestructure of compound 55:

In another embodiment, a compound of formula XI (e) is represented bythe structure of compound 17ya:

In another embodiment, a compound of formula XI (e) is represented bythe structure of compound 17yab:

In another embodiment, a compound of formula XI (e) is represented bythe structure of compound 17yac:

In one embodiment, this invention provides a compound represented by thefollowing structures:

com- pound structure  8

 9

10

11

12

13

14

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

32

33

34

35

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

In one embodiment the A, A′ and/or C groups of formula I, I(a), IV, IX,IX(a) and XI are independently substituted and unsubstituted furanyl,benzofuranyl, benzothiophenyl, indolyl, pyridinyl, phenyl, biphenyl,triphenyl, diphenylmethane, adamantane-yl, fluorene-yl, and otherheterocyclic analogs such as, e.g., pyrrolyl, pyrazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,pyrrolizinyl, indolyl, isoquinolinyl, quinolinyl, isoquinolinyl,benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinalolinyl,phthalazinyl, naphthyridinyl, quinoxalinyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium,benzodioxolyl, thiranyl, thietanyl, tetrahydrothiophene-yl, dithiolanyl,tetrahydrothiopyranyl, thiophene-yl, thiepinyl, thianaphthenyl,oxathiolanyl, morpholinyl, thioxanyl, thiazolyl, isothiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl).

In one embodiment, the A, A′ and/or C groups is substituted andunsubstituted phenyl. In another embodiment, the A, A′ and/or C groupsis phenyl substituted by Cl, F or methyl. In one embodiment, the A, A′and/or C groups is substituted and unsubstituted isoquinolinyl. In oneembodiment, the A, A′ and/or C groups include substituted andunsubstituted indolyl groups; most preferably, substituted andunsubstituted 3-indolyl and 5-indolyl.

In one embodiment, the A, A′ and/or C groups of formula I, I(a), IV, IX,IX(a) and XI can be substituted or unsubstituted. Thus, although theexemplary groups recited in the preceding paragraph are unsubstituted,it should be appreciated by those of skill in the art that these groupscan be substituted by one or more, two or more, three or more, and evenup to five substituents (other than hydrogen).

In one embodiment, the most preferred A, A′ and/or C groups aresubstituted by 3,4,5-trimethoxyphenyl. In another embodiment the A, A′and/or C groups are substituted by alkoxy. In another embodiment the A,A′ and/or C groups are substituted by methoxy. In another embodiment theA, A′ and/or C groups are substituted by alkyl. In another embodimentthe A, A′ and/or C groups are substituted by methyl. In anotherembodiment the A, A′ and/or C groups are substituted by halogen. Inanother embodiment, the A, A′ and/or C groups are substituted by F. Inanother embodiment, the A, A′ and/or C groups are substituted by Cl. Inanother embodiment,

the A, A′ and/or C rings are substituted by Br.

The substituents of these A, A′ and/or C groups of formula I, I(a), IV,IX, IX(a) and XI are independently selected from the group of hydrogen(e.g., no substitution at a particular position), hydroxyl, an aliphaticstraight- or branched-chain C₁ to C₁₀ hydrocarbon, alkoxy, haloalkoxy,aryloxy, nitro, cyano, alkyl-CN, halo, haloalkyl, dihaloalkyl,trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H, C(O)NH₂,—OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl, alkylamino, mesylamino,dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea,alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C₅ toC₇ cycloalkyl, arylalkyl, and combinations thereof. Single substituentscan be present at the ortho, meta, or para positions. When two or moresubstituents are present, one of them is preferably, though notnecessarily, at the para position.

In one embodiment the B group of formula I, I(a), II, III, IV, IVa and Vis selected from substituted or unsubstituted-thiazole, thiazolidine,oxazole, oxazoline, oxazolidine, benzene, pyrimidine, imidazole,pyridine, furan, thiophene, isoxazole, piperidine, pyrazole, indole andisoquinoline, wherein said B ring is linked via any two positions of thering to X and Y or directly to the A and/or C rings.

In one embodiment the B group of formula I, I(a), II, III, IV, IVa and Vis unsubstituted. In another embodiment the B group of formula I, I(a),II, III, IV, IVa and V is:

In another embodiment the B group of formula I, I(a), II, III, IV, IVaand V is substituted. In another embodiment the B group of formula I,I(a), II, III, IV, IVa and V is:

wherein R₁₀ and R₁₁ are independently hydrogen, O-alkyl, O-haloalkyl, F,Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂.

In another embodiment the B group is

(thiazole). In another embodiment the B group is

(thiazole). In another embodiment the B group is

(thiazolidine). In another embodiment the B group is

(oxazole). In another embodiment the B group is

(oxazoline). In another embodiment the B group is

(oxazolidine). In another embodiment the B group is

(benzene). In another embodiment the B group is

(benzene). In another embodiment the B group is

(pyrimidine). In another embodiment the B group is

(imidazole). In another embodiment the B group is

(pyridine). In another embodiment the B group is

(furan). In another embodiment the B group is

(thiophene). In another embodiment the B group is

(isoxazole). In another embodiment the B group is

(piperidine). In another embodiment the B group is

(piperidine). In another embodiment the B group is

(pyrazole). In another embodiment the B group is

(indole). In another embodiment the B group is

(isoquinoline).

In one embodiment the B group of formula I, I(a), II, III, IV, IVa and Vis substituted by R₁₀ and R₁₁. In another embodiment, R₁₀ and R₁₁ areboth hydrogens. In another embodiment, R₁₀ and R₁₁ are independentlyO-alkyl. In another embodiment, R₁₀ and R₁₁ are independentlyO-haloalkyl. In another embodiment, R₁₀ and R₁₁ are independently F. Inanother embodiment, R₁₀ and R₁₁ are independently Cl. In anotherembodiment, R₁₀ and R₁₁ are independently Br. In another embodiment, R₁₀and R₁₁ are independently I. In another embodiment, R₁₀ and R₁₁ areindependently haloalkyl. In another embodiment, R₁₀ and R₁₁ areindependently CF₃. In another embodiment, R₁₀ and R₁₁ are independentlyCN. In another embodiment, R₁₀ and R₁₁ are independently —CH₂CN. Inanother embodiment, R₁₀ and R₁₁ are independently NH₂. In anotherembodiment, R₁₀ and R₁₁ are independently hydroxyl. In anotherembodiment, R₁₀ and R₁₁ are independently —(CH₂)_(i)NHCH₃. In anotherembodiment, R₁₀ and R₁₁ are independently —(CH₂)_(i)NH₂. In anotherembodiment, R₁₀ and R₁₁ are independently —(CH₂)_(i)N(CH₃)₂. In anotherembodiment, R₁₀ and R₁₁ are independently —OC(O)CF₃. In anotherembodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear or branchedalkyl. In another embodiment, R₁₀ and R₁₁ are independently C₁-C₅ linearor branched haloalkyl. In another embodiment, R₁₀ and R₁₁ areindependently C₁-C₅ linear or branched alkylamino. In anotherembodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear or branchedaminoalkyl. In another embodiment, R₁₀ and R₁₁ are independently—OCH₂Ph. In another embodiment, R₁₀ and R₁₁ are independently—NHCO-alkyl. In another embodiment, R₁₀ and R₁₁ are independently COOH.In another embodiment, R₁₀ and R₁₁ are independently —C(O)Ph. In anotherembodiment, R₁₀ and R₁₁ are independently C(O)O-alkyl. In anotherembodiment, R₁₀ and R₁₁ are independently C(O)H. In another embodiment,R₁₀ and R₁₁ are independently —C(O)NH₂. In another embodiment, R₁₀ andR₁₁ are independently NO₂.

In another embodiment the B group of formula I, I(a), II, III, IV, IVaand V is

(thiazole), wherein R₁₀ and R₁₁ are independently H and 1 is 1. Inanother embodiment, R₁₀ and R₁₁ are independently O-alkyl. In anotherembodiment, R₁₀ and R₁₁ are independently O-haloalkyl. In anotherembodiment, R₁₀ and R₁₁ are independently F. In another embodiment, R₁₀and R₁₁ are independently Cl. In another embodiment, R₁₀ and R₁₁ areindependently Br. In another embodiment, R₁₀ and R₁₁ are independentlyI. In another embodiment, R₁₀ and R₁₁ are independently haloalkyl. Inanother embodiment, R₁₀ and R₁₁ are independently CF₃. In anotherembodiment, R₁₀ and R₁₁ are independently CN. In another embodiment, R₁₀and R₁₁ are independently —CH₂CN. In another embodiment, R₁₀ and R₁₁ areindependently NH₂. In another embodiment, R₁₀ and R₁₁ are independentlyhydroxyl. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NHCH₃. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NH₂. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁₀ and R₁₁ are independently—OC(O)CF₃. In another embodiment, R₁₀ and R₁₁ are independently C₁-C₅linear or branched alkyl. In another embodiment, R₁₀ and R₁₁ areindependently C₁-C₅ linear or branched haloalkyl. In another embodiment,R₁₀ and R₁₁ are independently C₁-C₅ linear or branched alkylamino. Inanother embodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear orbranched aminoalkyl. In another embodiment, R₁₀ and R₁₁ areindependently —OCH₂Ph. In another embodiment, R₁₀ and R₁₁ areindependently —NHCO-alkyl. In another embodiment, R₁₀ and R₁₁ areindependently COOH. In another embodiment, R₁₀ and R₁₁ are independently—C(O)Ph. In another embodiment, R₁₀ and R₁₁ are independentlyC(O)O-alkyl. In another embodiment, R₁₀ and R₁₁ are independently C(O)H.In another embodiment, R₁₀ and R₁₁ are independently —C(O)NH₂. Inanother embodiment, R₁₀ and R₁₁ are independently NO₂.

In another embodiment the B group of formula I, I(a), II, III, IV, IVaand V is

(imidazole), wherein R₁₀ and R₁₁ are independently H and l is 1. Inanother embodiment, R₁₀ and R₁₁ are independently O-alkyl. In anotherembodiment, R₁₀ and R₁₁ are independently O-haloalkyl. In anotherembodiment, R₁₀ and R₁₁ are independently F. In another embodiment, R₁₀and R₁₁ are independently Cl. In another embodiment, R₁₀ and R₁₁ areindependently Br. In another embodiment, R₁₀ and R₁₁ are independentlyI. In another embodiment, R₁₀ and R₁₁ are independently haloalkyl. Inanother embodiment, R₁₀ and R₁₁ are independently CF₃. In anotherembodiment, R₁₀ and R₁₁ are independently CN. In another embodiment, R₁₀and R₁₁ are independently —CH₂CN. In another embodiment, R₁₀ and R₁₁ areindependently NH₂. In another embodiment, R₁₀ and R₁₁ are independentlyhydroxyl. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NHCH₃. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NH₂. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁₀ and R₁₁ are independently—OC(O)CF₃. In another embodiment, R₁₀ and R₁₁ are independently C₁-C₅linear or branched alkyl. In another embodiment, R₁₀ and R₁₁ areindependently C₁-C₅ linear or branched haloalkyl. In another embodiment,R₁₀ and R₁₁ are independently C₁-C₅ linear or branched alkylamino. Inanother embodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear orbranched aminoalkyl. In another embodiment, R₁₀ and R₁₁ areindependently —OCH₂Ph. In another embodiment, R₁₀ and R₁₁ areindependently —NHCO-alkyl. In another embodiment, R₁₀ and R₁₁ areindependently COOH. In another embodiment, R₁₀ and R₁₁ are independently—C(O)Ph. In another embodiment, R₁₀ and R₁₁ are independentlyC(O)O-alkyl. In another embodiment, R₁₀ and R₁₁ are independently C(O)H.In another embodiment, R₁₀ and R₁₁ are independently —C(O)NH₂. Inanother embodiment, R₁₀ and R₁₁ are independently NO₂.

In another embodiment the B group of formula I, I(a), II, III, IV, IVaand V is

(isoquinoline), wherein R₁₀ and R₁₁ are independently H and l is 1. Inanother embodiment, R₁₀ and R₁₁ are independently O-alkyl. In anotherembodiment, R₁₀ and R₁₁ are independently O-haloalkyl. In anotherembodiment, R₁₀ and R₁₁ are independently F. In another embodiment, R₁₀and R₁₁ are independently Cl. In another embodiment, R₁₀ and R₁₁ areindependently Br. In another embodiment, R₁₀ and R₁₁ are independentlyI. In another embodiment, R₁₀ and R₁₁ are independently haloalkyl. Inanother embodiment, R₁₀ and R₁₁ are independently CF₃. In anotherembodiment, R₁₀ and R₁₁ are independently CN. In another embodiment, R₁₀and R₁₁ are independently —CH₂CN. In another embodiment, R₁₀ and R₁₁ areindependently NH₂. In another embodiment, R₁₀ and R₁₁ are independentlyhydroxyl. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NHCH₃. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)NH₂. In another embodiment, R₁₀ and R₁₁ are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁₀ and R₁₁ are independently—OC(O)CF₃. In another embodiment, R₁₀ and R₁₁ are independently C₁-C₅linear or branched alkyl. In another embodiment, R₁₀ and R₁₁ areindependently C₁-C₅ linear or branched haloalkyl. In another embodiment,R₁₀ and R₁₁ are independently C₁-C₅ linear or branched alkylamino. Inanother embodiment, R₁₀ and R₁₁ are independently C₁-C₅ linear orbranched aminoalkyl. In another embodiment, R₁₀ and R₁₁ areindependently —OCH₂Ph. In another embodiment, R₁₀ and R₁₁ areindependently —NHCO-alkyl. In another embodiment, R₁₀ and R₁₁ areindependently COOH. In another embodiment, R₁₀ and R₁₁ are independently—C(O)Ph. In another embodiment, R₁₀ and R₁₁ are independentlyC(O)O-alkyl. In another embodiment, R₁₀ and R₁₁ are independently C(O)H.In another embodiment, R₁₀ and R₁₁ are independently —C(O)NH₂. Inanother embodiment, R₁₀ and R₁₁ are independently NO₂.

In one embodiment, the X bridge of formula I, Ia, II, III, IV, IVa andXI is a bond. In another embodiment, the X bridge is NH. In anotherembodiment, the X bridge is C₁ to C₅ hydrocarbon. In another embodiment,the X bridge is CH₂. In another embodiment, the X bridge is —CH₂—CH₂—.In another embodiment, the X bridge is O. In another embodiment, the Xbridge is S.

In one embodiment, the Y bridge of formula I, Ia, II, III, IV, IVa, VI,and VII is C═O. In another embodiment, the Y bridge is C═S. In anotherembodiment, the Y bridge is C═N(NH₂)—. In another embodiment, the Ybridge is —C═NOH. In another embodiment, the Y bridge is —CH—OH. Inanother embodiment, the Y bridge is —C═CH—(CN). In another embodiment,the Y bridge is —C═N(CN). In another embodiment, the Y bridge is—C═C(CH₃)₂. In another embodiment, the Y bridge is —C═N-OMe. In anotherembodiment, the Y bridge is —(C═O)NH—. In another embodiment, the Ybridge is —NH(C═O)—. In another embodiment, the Y bridge is —(C═O)—O. Inanother embodiment, the Y bridge is —O—(C═O). In another embodiment, theY bridge is —(CH₂)₁₋₅—(C═O). In another embodiment, the Y bridge is—(C═O)—(CH₂)₁₋₅. In another embodiment, the Y bridge is S. In anotherembodiment, the Y bridge is SO. In another embodiment, the Y bridge isSO₂. In another embodiment, the Y bridge is —CH═CH—. In anotherembodiment, the Y bridge is —(SO₂)—NH—. In another embodiment, the Ybridge is —NH—(SO₂)—.

In one embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ of formula Ia, II, III, IV,IV(a), V, VI, VIII, IX, IX(a), XI(a), XI(b), XI(c), XI(d) and XI(e) areindependently hydrogen. In another embodiment, R₁, R₂, R₃, R₄, R₅ and R₆are independently O-alkyl. In another embodiment, R₁, R₂, R₃, R₄, R₅ andR₆ are independently O-haloalkyl. In another embodiment, R₁, R₂, R₃, R₄,R₅ and R₆ are independently F. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently Cl. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently Br. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently I. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently haloalkyl. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently CF₃. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently CN. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently —CH₂CN. In another embodiment, R₁, R₂,R₃, R₄, R₅ and R₆ are independently NH₂. In another embodiment, R₁, R₂,R₃, R₄, R₅ and R₆ are independently hydroxyl. In another embodiment, R₁,R₂, R₃, R₄, R₅ and R₆ are independently —(CH₂)_(i)NHCH₃. In anotherembodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently —(CH₂)_(i)NH₂.In another embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ areindependently —OC(O)CF₃. In another embodiment, R₁, R₂, R₃, R₄, R₅ andR₆ are independently C₁-C₅ linear or branched alkyl. In anotherembodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently haloalkyl. Inanother embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independentlyalkylamino. In another embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ areindependently aminoalkyl. In another embodiment, R₁, R₂, R₃, R₄, R₅ andR₆ are independently —OCH₂Ph. In another embodiment, R₁, R₂, R₃, R₄, R₅and R₆ are independently —NHCO-alkyl. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently COOH. In another embodiment, R₁, R₂, R₃,R₄, R₅ and R₆ are independently —C(O)Ph. In another embodiment, R₁, R₂,R₃, R₄, R₅ and R₆ are independently C(O)O-alkyl. In another embodiment,R₁, R₂, R₃, R₄, R₅ and R₆ are independently C(O)H. In anotherembodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently —C(O)NH₂. Inanother embodiment, R₁, R₂, R₃, R₄, R₅ and R₆ are independently NO₂.

In one embodiment, this invention is directed to a compound of formulaXII:

wherein,P and Q are independently H or

W is C═O, C═S, SO₂ or S═O;

wherein at least one of Q or P is not hydrogen;R₁ and R₄ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂; C(O)O-alkyl or C(O)H; wherein at leastone of R₁ and R₄ is not hydrogen;R₂ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl orC(O)H;m is an integer between 1-4;i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound of formulaXIII.

wherein

Z is O or S;

R₁ and R₄ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, haloalkyl, aminoalkyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂; COOH, C(O)O-alkyl orC(O)H; wherein at least one of R₁ and R₄ is not hydrogen;R₂ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂; OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;m is an integer between 1-4;i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, this invention is directed to a compound of formulaXIV:

wherein R₁ and R₄ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H; wherein at least one of R₁ and R₄ is not hydrogen;R₂ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl orC(O)H;m is an integer between 1-4;i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₁ of compound of formula XII, XIII and XIV is OCH₃.In another embodiment, R₁ of compound of formula XII, XIII and XIV is4-F. In another embodiment, R₁ of compound of formula XII, XIII and XIVis OCH₃ and m is 3. In another embodiment, R₄ of compound of formulaXII, XIII and XIV is 4-F. In another embodiment, R₄ of compound offormula XII, XIII and XIV is OCH₃. In another embodiment, R₄ of compoundof formula XIV is CH₃. In another embodiment, R₄ of compound of formulaXII, XIII and XIV is 4-Cl. In another embodiment, R₄ of compound offormula XII, XIII and XIV is 4-N(Me)₂. In another embodiment, R₄ ofcompound of formula XII, XIII and XIV is OBn. In another embodiment, R₄of compound of formula XII, XIII and XIV is 4-Br. In another embodiment,R₄ of compound of formula XII, XIII and XIV is 4-CF₃. Non limitingexamples of compounds of formula XIV are selected from:(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa),(4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af),(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba),(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca), (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone(12cb), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da), (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12db),(4-hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone(12dc),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12M),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-hydroxy-3,5-dimethoxyphenyl)methanone(12fc),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga);(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gb),(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ha),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12jb),(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la),(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa).

In one embodiment, this invention is directed to a compound of formulaXIVa:

wherein R₁ and R₄ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H; wherein at least one of R₁ and R₄ is not hydrogen;R₂ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;R₉ is H, linear or branched, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;wherein substitutions are independently selected from the group ofhydrogen (e.g., no substitution at a particular position), hydroxyl, analiphatic straight- or branched-chain C₁ to C₁₀ hydrocarbon, alkoxy,haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo, haloalkyl,dihaloalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H,C(O)NH₂, —OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl, alkylamino, mesylamino,dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea,alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C₅ toC₇ cycloalkyl, arylalkyl, and combinations thereof;m is an integer between 1-4;i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₉ of compound of formula XIVa is CH₃. In anotherembodiment, R₉ of compound of formula XIVa is —CH₂Ph. In anotherembodiment, R₉ of compound of formula XIVa is (SO₂)Ph. In anotherembodiment, R₉ of compound of formula XIVa is (SO₂)-Ph-OCH₃. In anotherembodiment, R₉ of compound of formula XIVa is H. In another embodiment,R₄ of compound of formula XIVa is H. In another embodiment, R₄ ofcompound of formula XIVa is CH₃. In another embodiment, R₄ of compoundof formula XIVa is OCH₃. In another embodiment, R₄ of compound offormula XIVa is OH. In another embodiment, R₄ of compound of formulaXIVa is 4-Cl. In another embodiment, R₄ of compound of formula XIVa is4-N(Me)₂. In another embodiment, R₄ of compound of formula XIVa is OBn.In another embodiment, R₁ of compound of formula XIVa is OCH₃; m is 3and R₂ is H. In another embodiment, R₁ of compound of formula XIVa is F;m is 1 and R₂ is H. Non limiting examples of compounds of formula XIVaare selected from:(4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11af),(4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11cb),(4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)methanone(11db),(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11fb),(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ga),(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11gb),(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ha),(2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11jb), (2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12gba),(1-benzyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12daa),(1-methyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12dab),(4-fluorophenyl)(2-(4-methoxyphenyl)-1-methyl-1H-imidazol-4-yl)methanone(12cba),(2-(4-ethylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12q),(2-(4-isopropylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12v),(2-(4-tert-butylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12w).

In one embodiment, this invention is directed to a compound of formulaXV:

wherein R₄ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;i is an integer between 0-5; andn is an integer between is 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₄ of compound of formula XV is H. In anotherembodiment, R₄ of compound of formula XV is F. In another embodiment, R₄of compound of formula XV is Cl. In another embodiment, R₄ of compoundof formula XV is Br. In another embodiment, R₄ of compound of formula XVis I. In another embodiment, R₄ of compound of formula XV is N(Me)₂. Inanother embodiment, R₄ of compound of formula XV is OBn. In anotherembodiment, R₄ of compound of formula XV is OCH₃. In another embodiment,R₄ of compound of formula XV is CH₃. In another embodiment, R₄ ofcompound of formula XV is CF₃. Non limiting examples of compounds offormula XV are selected from:(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa),(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba),(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da),(3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12ea),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga),(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ha),(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ia),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ja),(2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ka),(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la),(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa),(2-(4-ethylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12q),(2-(4-isopropylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12v), and(2-(4-tert-butylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12w).

In one embodiment, this invention is directed to a compound of formulaXVI:

wherein R₄ and R₅ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;

R₃ is I, Br, Cl, or F;

i is an integer between 0-5; andn is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₃ of compound of formula XVI is halogen. In anotherembodiment, R₃ is F. In another embodiment, R₃ is Cl. In anotherembodiment R₃ is Br. In another embodiment R₃ is I. In anotherembodiment R₄ is H. In another embodiment R₄ is OCH₃. In anotherembodiment R₄ is OCH₃; n is 3 and R₅ is H. In another embodiment R₄ isCH₃. In another embodiment R₄ is F. In another embodiment R₄ is Cl. Inanother embodiment R₄ is Br. In another embodiment R₄ is I. In anotherembodiment R₄ is N(Me)₂. In another embodiment R₄ is OBn. In anotherembodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-Cl. In anotherembodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-OCH₃. In anotherembodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-CH₃. In anotherembodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-N(Me)₂. Inanother embodiment, R₃ is F; R₅ is hydrogen; n is 1 and R₄ is 4-OBn. Nonlimiting examples of compounds of formula XVI are selected from:(4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af),(4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone (12cb),(4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12db),4-fluorophenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12eb), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12fb),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gb),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12jb).

In one embodiment, this invention is directed to a compound of formulaXVII:

wherein R₄ is H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl,—OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;wherein R₁ and R₂ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH,C(O)O-alkyl or C(O)H;andm is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₄ of compound of formula XVII is halogen. In anotherembodiment, R₄ is F. In another embodiment, R₄ is Cl. In anotherembodiment R₄ is Br. In another embodiment R₄ is I. In anotherembodiment, R₄ is OCH₃. In another embodiment, R₄ is CH₃. In anotherembodiment, R₄ is N(Me)₂. In another embodiment, R₄ is CF₃. In anotherembodiment, R₄ is OH. In another embodiment, R₄ is OBn. In anotherembodiment, R₁ of compound of formula XVII is halogen. In anotherembodiment, R₁ of compound of formula XVII is F. In another embodiment,R₁ of compound of formula XVII is Cl. In another embodiment, R₁ ofcompound of formula XVII is Br. In another embodiment, R₁ of compound offormula XVII is I. In another embodiment, R₁ of compound of formula XVIIis OCH₃. In another embodiment, R₁ of compound of formula XVII is OCH₃,m is 3 and R₂ is H. In another embodiment, R₁ of compound of formulaXVII is F, m is 1 and R₂ is H. In another embodiment, R₄ is F; R₂ ishydrogen; n is 3 and R₁ is OCH₃. In another embodiment, R₄ is OCH₃; R₂is hydrogen; n is 3 and R₁ is OCH₃. In another embodiment, R₄ is CH₃; R₂is hydrogen; n is 3 and R₁ is OCH₃. In another embodiment, R₄ is Cl; R₂is hydrogen; n is 3 and R₁ is OCH₃. In another embodiment, R₄ is N(Me)₂;R₂ is hydrogen; n is 3 and R₁ is OCH₃. In one embodiment, R₄ of compoundof formula XVII is halogen, R₁ is H and R₂ is halogen. In oneembodiment, R₄ of compound of formula XVII is halogen, R₁ is halogen andR₂ is H. In one embodiment, R₄ of compound of formula XVII is alkoxy, R₁is halogen and R₂ is H. In one embodiment, R₄ of compound of formulaXVII is methoxy, R₁ is halogen and R₂ is H. Non limiting examples ofcompounds of formula XVII are selected from:(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba),(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca), (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone(12cb), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da), (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12db),(4-Hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone(12dc),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa), (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12fb),(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone(13fa),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gb),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12jb),(2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ka),(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la),(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa),(2-(4-ethylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12q),(2-(4-isopropylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12v), and(2-(4-tert-butylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12w).

In another embodiment a compound of formula XVII is represented by thestructure of formula 12fb:

In another embodiment a compound of formula XVII is represented by thestructure of formula 12cb:

In one embodiment, this invention is directed to a compound of formulaXVIII:

wherein

W is C═O, C═S, SO₂ or S═O;

R₄ and R₇ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;R₅ and R₃ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;n is an integer between 1-4;i is an integer between 0-5; andq is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, W of compound of formula XVIII is C═O. In anotherembodiment, W of compound of formula XVIII 15 SO₂. In anotherembodiment, R₄ of compound of formula XVIII is H. In another embodiment,R₄ of compound of formula XVIII is NO₂. In another embodiment, R₄ ofcompound of formula XVIII is OBn. In another embodiment, R₇ of compoundof formula XVIII is H. In another embodiment, R₇ of compound of formulaXVIII is OCH₃. In another embodiment, R₇ of compound of formula XVIII isOCH₃ and q is 3. Non limiting examples of compounds of formula XVII areselected from: (4-methoxyphenyl)(2-phenyl-1H-imidazol-1-yl)methanone(12aba), (2-phenyl-1H-imidazol-1-yl)(3,4,5-trimethoxyphenyl)methanone(12aaa), 2-phenyl-1-(phenylsulfonyl)-1H-imidazole (10a),2-(4-nitrophenyl)-1-(phenylsulfonyl)-1H-imidazole (10x),2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazole (10j).

In one embodiment, this invention is directed to a compound of formulaXIX:

wherein

W is C═O, C═S, SO₂, S═O;

R₁, R₄ and R₇ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;R₂, R₅ and R₃ are independently H, O-alkyl, I, Br, Cl, F, alkyl,haloalkyl, aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂,—(CH₂)_(i)N(CH₃)₂, —OCH₂Ph, OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkylor C(O)H;m is an integer between 1-4;n is an integer between 1-4;i is an integer between 0-5; andq is 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₁, R₄ and R₇ of formula XIX are independently H. Inanother embodiment, R₁, R₄ and R₇ of formula XIX are independentlyO-alkyl. In another embodiment, R₁, R₄ and R₇ of formula XIX areindependently halogen. In another embodiment, R₁, R₄ and R₇ of formulaXIX are independently CN. In another embodiment, R₁, R₄ and R₇ offormula XIX are independently OH. In another embodiment, R₁, R₄ and R₇of formula XIX are independently alkyl. In another embodiment, R₁, R₄and R₇ of formula XIX are independently —OCH₂Ph. In one embodiment R₂,R₅ and R₈ of formula XIX are independently H. In another embodiment, R₂,R₅ and R₈ of formula XIX are independently O-alkyl. In anotherembodiment, R₂, R₅ and R₈ of formula XIX are independently halogen. Inanother embodiment, R₂, R₅ and R₈ of formula XIX are independently CN.In another embodiment, R₂, R₅ and R₈ of formula XIX are independentlyOH. In another embodiment, R₂, R₅ and R₈ of formula XIX areindependently alkyl. In another embodiment, R₂, R₅ and R₈ of formula XIXare independently —OCH₂Ph. In another embodiment, R₅, R₂ and R₈ offormula XIX are H, R₄ is 4-N(Me)₂, R₁ is OCH₃, m is 3 and R₇ is OCH₃. Inanother embodiment, R₅, R₂, R₇ and R₈ of formula XIX are H, R₄ is 4-Br,R₁ is OCH₃, and m is 3. In another embodiment W is SO₂. In anotherembodiment W is C═O. In another embodiment W is C═S. In anotherembodiment W is S═O, Non limiting examples of compounds of formula XIXare selected from: (2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11gaa);(2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11la),(4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11cb),(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11fb),(4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11af),(4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)methanone(11db),(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ga),(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11gb),(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ha),(2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11jb),(2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gba).

In another embodiment a compound of formula XIX is represented by thestructure of formula 11cb:

In another embodiment a compound of formula XIX is represented by thestructure of formula 11fb:

In one embodiment, this invention is directed to a compound of formulaXX:

whereinR₄ is H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl, aminoalkyl,—(CH₂)_(i)NHCH₃, —(CH₂)₁NH₂, —(CH₂)_(i)N(CH₃)₂, —OCH₂Ph, OH, CN, NO₂,—NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H; andi is an integer between 0-5;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₄ of compound of formula XX is H. In anotherembodiment, R₄ of compound of formula XX is halogen. In anotherembodiment, R₄ is F. In another embodiment, R₄ is Cl. In anotherembodiment R₄ is Br. In another embodiment R₄ is I. In anotherembodiment, R₄ is alkyl. In another embodiment, R₄ is methyl. Nonlimiting examples of compounds of formula XX are selected from:(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa),(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba),(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca), (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da),(2-(4-chlorophenyl)-1H-imidazol-4-(3,4,5-trimethoxyphenyl)methanone(12fa),(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-(3,4,5-trimethoxyphenyl)methanone(12ga),(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ia),(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ja),(2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ka),(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la),(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa),(2-(4-ethylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12q),(2-(4-isopropylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12v), and(2-(4-tert-butylphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12w).

In another embodiment a compound of formula XX is represented by thestructure of formula 12da:

In another embodiment a compound of formula XX is represented by thestructure of formula 12fa:

In one embodiment, this invention is directed to a compound of formulaXXI:

whereinA is indolyl;

Q is NH, O or S;

R₁ and R₂ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H; andwherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)₁NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;i is an integer between 0-5; andm is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₁ of compound of formula XXI is OCH₃; m is 3 and R₂is hydrogen. In another embodiment, R₁ is F; m is 1 and R₂ is hydrogen.In one embodiment, Q of formula XXI is O. In another embodiment Q offormula XXI is NH. In another embodiment, Q of formula XXI is S.

In one embodiment, A ring of compound of formula XXI is substituted5-indolyl. In another embodiment the substitution is —(C═O)-aryl. Inanother embodiment, the aryl is 3,4,5-(OCH₃)₃-Ph.

In another embodiment, A ring of compound of formula XXI is 3-indolyl.In another embodiment, A ring of compound of formula XXI is 5-indolyl.In another embodiment, A ring of compound of formula XXI is 2-indolyl.Non limiting examples of compounds of formula XXI are selected from:(5-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa);(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa);2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya); (2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(62a); and(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (66a).

In one embodiment, this invention is directed to a compound of formulaXXIa:

wherein

W is C═O, C═S, SO₂, S═O;

A is indolyl;R₁ and R₂ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;R₇ and R₈ are independently H, O-alkyl, I, Br, Cl, F, alkyl, haloalkyl,aminoalkyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OCH₂Ph,OH, CN, NO₂, —NHCO-alkyl, COOH, C(O)O-alkyl or C(O)H;wherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;i is an integer between 0-5; andm is an integer between 1-4;q is an integer between 1-4;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, R₁ of compound of formula XXIa is OCH₃; m is 3 and R₂is hydrogen. In another embodiment, R₁ is F; m is 1 and R₂ is hydrogen.In another embodiment, A ring of compound of formula XXIa is substituted5-indolyl. In another embodiment, A ring of compound of formula XXIa is3-indolyl. Non limiting examples of compounds of formula XXIa areselected from:(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa);(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yaa).

In one embodiment, this invention is directed to a compound of formulaXXII:

whereinA is indolyl;wherein said A is optionally substituted by substituted or unsubstitutedO-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂,hydroxyl, —(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃,substituted or unsubstituted —SO₂-aryl, substituted or unsubstitutedC₁-C₅ linear or branched alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkylamino, substituted or unsubstitutedaminoalkyl, —OCH₂Ph, substituted or unsubstituted —NHCO-alkyl, COOH,substituted or unsubstituted —C(O)Ph, substituted or unsubstitutedC(O)O-alkyl, C(O)H, —C(O)NH₂, NO₂ or combination thereof;i is an integer between 0-5;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In one embodiment, A ring of compound of formula XXII is substituted5-indolyl. In another embodiment the substitution is —(C═O)-aryl. Inanother embodiment, the aryl is 3,4,5-(OCH₃)₃-Ph.

In another embodiment, A ring of compound of formula XXII is 3-indolyl.Non limiting examples of compounds of formula XXII are selected from:(5-(4-(3,4,5-trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa);(2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya).

In another embodiment a compound of formula XXI or XXII is representedby the structure of formula 17ya:

In one embodiment, this invention is directed to a compound of formulaXXIII:

whereinR₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₉ and R₁₂ are independently hydrogen, linear or branched, substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;wherein substitutions are independently selected from the group ofhydroxyl, an aliphatic straight- or branched-chain C₁ to C₁₀hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo,haloalkyl, dihaloalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl,C(O)O-alkyl, C(O)H, C(O)NH₂, —OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl,alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl,urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido,arylamido, aryl, and C₅ to C₇ cycloalkyl, arylalkyl, and combinationsthereof;X is a bond, NH, C₁ to C₅ hydrocarbon, O, or S;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;n is an integer between 1-3; andm is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In another embodiment, X of formula XXIII is a bond. In anotherembodiment, Y of formula XXIII is a C═O. In another embodiment X offormula XXIII is a bond and Y of formula XXIII is C═O. In anotherembodiment, R₉ and R₁₂ of formula XXIII are both hydrogens.

In one embodiment, this invention is directed to a compound of formulaXXIV:

whereinR₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₉ and R₁₂ are independently hydrogen, linear or branched, substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;wherein substitutions are independently selected from the group ofhydroxyl, an aliphatic straight- or branched-chain C₁ to C₁₀hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo,haloalkyl, dihaloalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl,C(O)O-alkyl, C(O)H, C(O)NH₂, —OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl,alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl,urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido,arylamido, aryl, and C₅ to C₇ cycloalkyl, arylalkyl, and combinationsthereof;Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN,—CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O),—(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S;i is an integer between 0-5;n is an integer between 1-3; andm is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

In another embodiment, Y of formula XXIV is C═O.

In another embodiment, R₉ and R₁₂ of formula XXIV are both hydrogens.

In one embodiment, this invention is directed to a compound of formulaXXV:

whereinR₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl, F, Cl,Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl, —(CH₂)_(i)NHCH₃,—(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅ linear or branchedalkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph, —NHCO-alkyl, COOH,—C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂;R₉ and R₁₂ are independently hydrogen, linear or branched, substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH;wherein substitutions are independently selected from the group ofhydroxyl, an aliphatic straight- or branched-chain C₁ to C₁₀hydrocarbon, alkoxy, haloalkoxy, aryloxy, nitro, cyano, alkyl-CN, halo,haloalkyl, dihaloalkyl, trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl,C(O)O-alkyl, C(O)H, C(O)NH₂, —OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl,alkylamino, mesylamino, dialkylamino, arylamino, amido, NHC(O)-alkyl,urea, alkyl-urea, alkylamido (e.g., acetamide), haloalkylamido,arylamido, aryl, and C₅ to C₇ cycloalkyl, arylalkyl, and combinationsthereof;i is an integer between 0-5;n is an integer between 1-3;or its pharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.

It is well understood that in structures presented in this inventionwherein the nitrogen atom has less than 3 bonds, H atoms are present tocomplete the valence of the nitrogen.

In another embodiment, the compound of formula XXIII, XXIV and/or XXV is

-   (4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone (70a);-   (4-(4-fluorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70b);-   (4-(4-chlorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70c);-   (4-(4-bromophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70d);-   (4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70e);-   (4-p-tolyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone (70f);-   (4-(4-methoxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70g);-   (4-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70h);-   (4-(4-hydroxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70i);-   (5-methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70j);-   (5-ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70k);-   (4-phenyl-5-propyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70l);-   (1-methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70m);-   (1-ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70n);-   (1-benzyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70o); or-   (1-cyclopentyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone    (70p).

In one embodiment, Q of compound of formula XII is H and P is

In another embodiment, P of compound of formula XII is H and Q is

In another embodiment, P of compound of formula XII is

and Q is SO₂-Ph. In one embodiment. Q of compound of formula XII is Hand P is

wherein W is C═O. In another embodiment W of compound of formula XII,XVIII, XIX, or XXIa is C═O. In another embodiment, W of compound offormula XII, XVIII, XIX, or XXIa is SO₂. In another embodiment, W ofcompound of formula XII, XVIII, XIX, or XXIa is C═S. In anotherembodiment, W of compound of formula XII, XVIII, XIX, or XXIa is S═O.

In one embodiment, Z of compound of formula XIII is oxygen. In anotherembodiment, Z of compound of formula XIII is sulfur.

In one embodiment, R₄ of compound of formula XII-XVI, XVIII, XIX orXXIII-XXV is hydrogen, n is 1 and R₄ is in the para position.

In one embodiment, R₄ of compound of formula XII-XX or XXIII-XXV isalkyl. In another embodiment, R₄ of compound of formula XII-XX orXXIII-XXV is H. In another embodiment, R₄ of compound of formula XII-XXor XXIII-XXV is methyl (CH₃). In another embodiment, R₄ of compound offormula XII-XX or XXIII-XXV is hydroxyl. In another embodiment, R₄ ofcompound of formula XII-XX or XXIII-XXV is ethyl. In another embodiment,R₄ of compound of formula XII-XX or XXIII-XXV is propyl. In anotherembodiment, R₄ of compound of formula XII-XX or XXIII-XXV is isopropyl.In another embodiment, R₄ of compound of formula XII-XX or XXIII-XXV istert-butyl. In another embodiment, R₄ of compound of formula XII-XX orXXIII-XXV is O-alkyl. In another embodiment, R₄ of compound of formulaXII-XX is OCH₃. In another embodiment, R₄ of compound of formula XII-XXor XXIII-XXV is I. In another embodiment, R₄ of compound of formulaXII-XX or XXIII-XXV is Br. In another embodiment, R₄ of compound offormula XII-XX or XXIII-XXV is F. In another embodiment, R₄ of compoundof formula XII-XX or XXIII-XXV is Cl. In another embodiment, R₄ ofcompound of formula XII-XX or XXIII-XXV is N(Me)₂. In anotherembodiment, R₄ of compound of formula XII-XX or XXIII-XXV is OBn. Inanother embodiment, R₄ of compound of formula XII-XX or XXIII-XXV is OH.In another embodiment, R₄ of compound of formula XII-XX or XXIII-XXV isCF₃.

In one embodiment, R₂ of compound of formula XII, XIII, XIV, XIVa, XVII,XIX, XXI or XXIa is hydrogen; R₁ is OCH₃ and m is 3. In anotherembodiment, R₂ of compound of formula XII, XIII, XIV, XIVa, XVII, XIX,XXI or XXIa is hydrogen; m is 1 and R₁ is in the para position. Inanother embodiment, R₂ of compound of formula XII, XIII, XIV, XIVa,XVII, XIX, XXI or XXIa is hydrogen; m is 1 and R₁ is I. In anotherembodiment, R₂ of compound of formula XII, XIII, XIV, XIVa, XVII, XIX,XXI or XXIa is hydrogen; m is 1 and R₁ is Br. In another embodiment, R₂of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa ishydrogen; m is 1 and R₁ is F. In another embodiment, R₂ of compound offormula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is hydrogen; m is 1and R₁ is Cl. In another embodiment, R₁ of compound of formula XII,XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is I. In another embodiment, R₁of compound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa isBr. In another embodiment, R₁ of compound of formula XII, XIII, XIV,XIVa, XVII, XIX, XXI or XXIa is Cl. In another embodiment, R₁ ofcompound of formula XII, XIII, XIV, XIVa, XVII, XIX, XXI or XXIa is F.

In one embodiment, R₁, R₂ and R₃ of formula XXIII or XXIV areindependently hydrogen. In another embodiment, R₁, R₂ and R₃ areindependently O-alkyl. In another embodiment, R₁, R₂ and R₃ areindependently methoxy. In another embodiment, R₁, R₂ and R₃ areindependently O-haloalkyl. In another embodiment, R₁, R₂ and R₃ areindependently F. In another embodiment, R₁, R₂ and R₃ are independentlyCl. In another embodiment, R₁, R₂ and R₃ are independently Br. Inanother embodiment, R₁, R₂ and R₃ are independently I. In anotherembodiment, R₁, R₂ and R₃ are independently haloalkyl. In anotherembodiment, R₁, R₂ and R₃ are independently CF₃. In another embodiment,R₁, R₂ and R₃ are independently CN. In another embodiment, R₁, R₂ and R₃are independently —CH₂CN. In another embodiment R₁, R₂ and R₃ areindependently NH₂. In another embodiment, R₁, R₂ and R₃ areindependently hydroxyl. In another embodiment, R₁, R₂ and R₃ areindependently —(CH₂)_(i)NHCH₃. In another embodiment, R₁, R₂ and R₃ areindependently —(CH₂)_(i)NH₂. In another embodiment, R₁, R₂ and R₃ areindependently —(CH₂)_(i)N(CH₃)₂. In another embodiment, R₁, R₂ and R₃are independently —OC(O)CF₃. In another embodiment, R₁, R₂ and R₃ areindependently C₁-C₅ linear or branched alkyl. In another embodiment, R₁,R₂ and R₃ are independently haloalkyl. In another embodiment, R₁, R₂ andR₃ are independently alkylamino. In another embodiment, R₁, R₂ and R₃are independently aminoalkyl. In another embodiment, R₁, R₂ and R₃ areindependently —OCH₂Ph. In another embodiment, R₁, R₂ and R₃ areindependently —NHCO-alkyl. In another embodiment, R₁, R₂ and R₃ areindependently COOH. In another embodiment, R₁, R₂ and R₃ areindependently —C(O)Ph. In another embodiment,

R₁, R₂ and R₃ are independently C(O)O-alkyl. In another embodiment, R₁,R₂ and R₃ are independently C(O)H. In another embodiment, R₁, R₂ and R₃are independently —C(O)NH₂. In another embodiment, R₁, R₂ and R₃ areindependently NO₂.

In another embodiment, m of formula XXIII and XXIV is 1. In anotherembodiment, m of formula XXIII and XXIV is 2. In another embodiment, mof formula XXIII and XXIV is 3. In another embodiment, R₁ of formulaXXIII and XXIV is O-alkyl, R₂ and R₃ are hydrogens and m is 3.

In one embodiment, R₄, R₅ and R₆ of formula XXIII-XXV are independentlyhydrogen.

In another embodiment, R₄, R₅ and R₆ of formula XXIII-XXV areindependently O-alkyl. In another embodiment, R₄, R₅ and R₆ of formulaXXIII-XXV are independently O-haloalkyl. In another embodiment, R₄, R₅and R₆ of formula XXIII-XXV are independently F. In another embodiment,R₄, R₅ and R₆ of formula XXIII-XXV are independently Cl. In anotherembodiment, R₄, R₅ and R₆ of formula XXIII-XXV are independently Br. Inanother embodiment, R₄, R₅ and R₆ of formula XXIII-XXV are independentlyI. In another embodiment, R₄, R₅ and R₆ of formula XXIII-XXV areindependently haloalkyl. In another embodiment, R₄, R₅ and R₆ of formulaXXIII-XXV are independently CF₃. In another embodiment, R₄, R₅ and R₆ offormula XXIII-XXV are independently CN. In another embodiment, R₄, R₅and R₆ of formula XXIII-XXV are independently —CH₂CN. In anotherembodiment, R₄, R₅ and R₆ of formula XXIII-XXV are independently NH₂. Inanother embodiment, R₄, R₅ and R₆ of formula XXIII-XXV are independentlyhydroxyl. In another embodiment, R₄, R₅ and R₆ of formula XXIII-XXV areindependently —(CH₂)_(i)NHCH₃. In another embodiment, R₄, R₅ and R₆ offormula XXIII-XXV are independently —(CH₂)_(i)NH₂. In anotherembodiment, R₄, R₅ and R₆ of formula XXIII-XXV are independently—(CH₂)_(i)N(CH₃)₂. In another embodiment, R₄, R₅ and R₆ of formulaXXIII-XXV are independently —OC(O)CF₃. In another embodiment, R₄, R₅ andR₆ of formula XXIII-XXV are independently C₁-C₅ linear or branchedalkyl. In another embodiment, R₄, R₅ and R₆ of formula XXIII-XXV areindependently haloalkyl. In another embodiment, R₄, R₅ and R₆ of formulaXXIII-XXV are independently alkylamino. In another embodiment, R₄, R₅and R₆ of formula XXIII-XXV are independently aminoalkyl. In anotherembodiment, R₄, R₅ and R₆ of formula XXIII-XXV are independently—OCH₂Ph. In another embodiment, R₄, R₅ and R₆ of formula XXIII-XXV areindependently —NHCO-alkyl. In another embodiment, R₄, R₅ and R₆ offormula XXIII-XXV are independently COOH. In another embodiment, R₄, R₅and R₆ of formula XXIII-XXV are independently —C(O)Ph. In anotherembodiment, R₄, R₅ and R₆ of formula XXIII-XXV are independentlyC(O)O-alkyl. In another embodiment, R₄, R₅ and R₆ of formula XXIII-XXVare independently C(O)H. In another embodiment, R₄, R₅ and R₆ of formulaXXIII-XXV are independently —C(O)NH₂. In another embodiment, R₄, R₅ andR₆ of formula XXIII-XXV are independently NO₂.

In another embodiment, n of formula XXIII-XXV is 1. In anotherembodiment, n of formula XXIII-XXV is 2. In another embodiment, n offormula XXIII-XXV is 3.

In one embodiment, R₉ and R₁₂ of formula XXIII-XXV is independentlyhydrogen. In another embodiment, R₉ and R₁₂ of formula XXIII-XXV isindependently a linear or branched alkyl. In another embodiment, R₉ andR₁₂ of formula XXIII-XXV is independently a methyl. In anotherembodiment, R₉ and R₁₂ of formula XXIII-XXV is an ethyl. In anotherembodiment, R₉ and R₁₂ of formula XXIII-XXV is a propyl. In anotherembodiment, R₉ and R₁₂ of formula XXIII-XXV is isopropyl. In anotherembodiment, R₉ and R₁₂ of formula XXIII-XXV is a tert-butyl. In anotherembodiment, R₉ and R₁₂ of formula XXIII-XXV is substituted orunsubstituted cycloalkyl. In another embodiment, R₉ and R₁₂ of formulaXXIII-XXV is cyclopentyl. In another embodiment, R₉ and R₁₂ of formulaXXIII-XXV is substituted or unsubstituted aryl. In another embodiment,R₉ and R₁₂ of formula XXIII-XXV is —CH₂Ph. In another embodiment, R₉ andR₁₂ of formula XXIII-XXV is substituted benzyl. In another embodiment,R₉ and R₁₂ of formula XXIII-XXV is haloalkyl. In another embodiment, R₉and R₁₂ of formula XXIII-XXV is aminoalkyl. In another embodiment, R₉and R₁₂ of formula XXIII-XXV is —OCH₂Ph. In another embodiment, R₉ andR₁₂ of formula XXIII-XXV is substituted or unsubstituted SO₂-aryl. Inanother embodiment, R₉ and R₁₂ of formula XXIII-XXV is substituted orunsubstituted —(C═O)-aryl. In another embodiment, R₉ and R₁₂ of formulaXXIII-XXV is OH.

In one embodiment Q of compound of formula XII is H and P is

wherein W is C═O, Non-limiting examples of compounds of formula XII-XVIIand XX-XXII are selected from(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa);(4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ab);(3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ac);(3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ad);(3,4-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ae);(4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af);(3-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ag);(2-phenyl-1H-imidazol-4-yl)(p-tolyl)methanone (12ah);(2-phenyl-1H-imidazol-4-yl)(m-tolyl)methanone (12ai);(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ba);(2-(4-methoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ca); (4-fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone(12cb); (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12da); (4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone (12db);(4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone hydrochloride(12db-HCl);(4-hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)-1H-imidazol-4-yl)methanone(12dc);(3,4,5-trimethoxyphenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12ea);(4-fluorophenyl)(2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(12eb);(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa); (2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12fb);(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4-hydroxy-3,5-dimethoxyphenyl)methanone(12fc);(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ga);(2-(4-(dimethylamino)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gb);(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ha);(2-(3,4-dimethoxyphenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12hb);(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ia);(4-fluorophenyl)(2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanone(12ib);(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ja);(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12jb);(2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12ka); (2-(4-(hydroxyphenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12kb);(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la);(2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12pa);(3,4,5-trihydroxyphenyl)(2-(3,4,5-trihydroxyphenyl)-1H-imidazol-4-yl)methanone(13ea);(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone(13fa); and2-(3,4-dihydroxyphenyl)-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanone(13ha).

In one embodiment, P of compound of formula XII is

and Q is SO₂-Ph. Non-limiting examples of compound of formula XIIwherein P of compound of formula XII is

and Q is SO₂-Ph are selected from(4-methoxyphenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11ab);(3-methoxyphenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11ac); (2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)(p-tolyl)methanone (11ah);(4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11af);(3-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11ag);(4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11cb);(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11da);(4-fluorophenyl)(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)methanone(11db);(1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ea);(4-fluorophenyl)(1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)methanone(11eb);(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11fb);(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ga);(2-(4-(dimethylamino)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11gb);(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ha);(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11hb);(1-(phenylsulfonyl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11ia);(1-(phenylsulfonyl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11ib); and(2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11jb);(2-(4-bromophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11la);(1-(phenylsulfonyl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11pa).

In one embodiment, R₄ and R₅ of compounds of formula XIII-XVI arehydrogens. Non-limiting examples of compounds of formula XIII-XVIwherein R₄ and R₅ are hydrogens are selected from(2-phenyl-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12aa);(4-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ab);(3-methoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ac);(3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ad);(3,4-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ae);(4-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12af);(3-fluorophenyl)(2-phenyl-1H-imidazol-4-yl)methanone (12ag);(2-phenyl-1H-imidazol-4-yl)(p-tolyl)methanone (12ah); and(2-phenyl-1H-imidazol-4-yl)(m-tolyl)methanone (12ai).

In one embodiment, P of compound of formula XII is H and Q is

In another embodiment W is C═O. In another embodiment, W of compound offormula XVIII is C═O, Non-limiting examples of compound of formula XVIIIwherein W is C═O are selected from(4-methoxyphenyl)(2-phenyl-1H-imidazol-1-yl)methanone (12aba) and(2-phenyl-1H-imidazol-1-yl)(3,4,5-trimethoxyphenyl)methanone (12aaa).

In another embodiment, W of compound of formula XVIII is SO₂.Non-limiting examples of compound of formula XVIII wherein W is SO₂ areselected from 2-phenyl-1-(phenylsulfonyl)-1H-imidazole (10a);2-(4-nitrophenyl)-1-(phenylsulfonyl)-1H-imidazole (10x) and2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)-1H-imidazole (10j).

As used herein, “single-, fused- or multiple-ring, aryl or(hetero)cyclic ring systems” can be any such ring, including but notlimited to phenyl, biphenyl, triphenyl, naphthyl, cycloalkyl,cycloalkenyl, cyclodienyl, fluorene, adamantane, etc.

“Saturated or unsaturated N-heterocycles” can be any such N-containingheterocycle, including but not limited to aza- and diaza-cycloalkylssuch as aziridinyl, azetidinyl, diazatidinyl, pyrrolidinyl, piperidinyl,piperazinyl, and azocanyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,indazolyl, quinolizinyl, cinnolinyl, quinololinyl, phthalazinyl,naphthyridinyl, quinoxalinyl, etc.

“Saturated or unsaturated O-Heterocycles” can be any such O-containingheterocycle including but not limited to oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium,benzofuranyl, benzodioxolyl, etc.

“Saturated or unsaturated S-heterocycles” can be any such S-containingheterocycle, including but not limited to thiranyl, thietanyl,tetrahydrothiophene-yl, dithiolanyl, tetrahydrothiopyranyl,thiophene-yl, benzothiophenyl, thiepinyl, thianaphthenyl, etc.

“Saturated or unsaturated mixed heterocycles” can be any heterocyclecontaining two or more S-, N-, or O-heteroatoms, including but notlimited to oxathiolanyl, morpholinyl, thioxanyl, thiazolyl,isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiaziolyl, etc.

As used herein, “aliphatic straight- or branched-chain hydrocarbon”refers to both alkylene groups that contain a single carbon and up to adefined upper limit, as well as alkenyl groups and alkynyl groups thatcontain two carbons up to the upper limit, whether the carbons arepresent in a single chain or a branched chain. Unless specificallyidentified, a hydrocarbon can include up to about 30 carbons, or up toabout 20 hydrocarbons, or up to about 10 hydrocarbons. Alkenyl andalkynyl groups can be mono-unsaturated or polyunsaturated. In anotherembodiment, an alkyl includes C₁-C₆ carbons. In another embodiment, analkyl includes C₁-C₈ carbons. In another embodiment, an alkyl includesC₁-C₁₀ carbons. In another embodiment, an alkyl is a C₁-C₁₂ carbons. Inanother embodiment, an alkyl is a C₁-C₅ carbons.

As used herein, the term “alkyl” can be any straight- or branched-chainalkyl group containing up to about 30 carbons unless otherwisespecified. In another embodiment, an alkyl includes C₁-C₆ carbons. Inanother embodiment, an alkyl includes C₁-C₈ carbons. In anotherembodiment, an alkyl includes C₁-C₁₀ carbons. In another embodiment, analkyl is a C₁-C₁₂ carbons. In another embodiment, an alkyl is a C₁-C₂₀carbons. In another embodiment, cyclic alkyl group has 3-8 carbons. Inanother embodiment, branched alkyl is an alkyl substituted by alkyl sidechains of 1 to 5 carbons.

The alkyl group can be a sole substituent or it can be a component of alarger substituent, such as in an alkoxy, haloalkyl, arylalkyl,alkylamino, dialkylamino, alkylamido, alkylurea, etc. Preferred alkylgroups are methyl, ethyl, and propyl, and thus halomethyl, dihalomethyl,trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl,dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl,arylethyl, arylpropyl, methylamino, ethylamino, propylamino,dimethylamino, diethylamino, methylamido, acetamido, propylamido,halomethylamido, haloethylamido, halopropylamido, methyl-urea,ethyl-urea, propyl-urea, etc.

As used herein, the term “aryl” refers to any aromatic ring that isdirectly bonded to another group. The aryl group can be a solesubstituent, or the aryl group can be a component of a largersubstituent, such as in an arylalkyl, arylamino, arylamido, etc.Exemplary aryl groups include, without limitation, phenyl, tolyl, xylyl,furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, thiazolyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl,thiophene-yl, pyrrolyl, phenylmethyl, phenylethyl, phenylamino,phenylamido, etc.

As used herein, the term “aminoalkyl” refers to an amine groupsubstituted by an alkyl group as defined above. Aminoalkyl refers tomonoalkylamine, dialkylamine or trialkylamine. Nonlimiting examples ofaminoalkyl groups are —N(Me)₂, —NHMe, —NH₃.

A “haloalkyl” group refers, in another embodiment, to an alkyl group asdefined above, which is substituted by one or more halogen atoms, e.g.by F, Cl, Br or I. Nonlimiting examples of haloalkyl groups are CF₃,CF₂CF₃, CH₂CF₃.

In one embodiment, this invention provides a compound of this inventionor its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, orcrystal or combinations thereof. In one embodiment, this inventionprovides an isomer of the compound of this invention. In anotherembodiment, this invention provides a metabolite of the compound of thisinvention. In another embodiment, this invention provides apharmaceutically acceptable salt of the compound of this invention. Inanother embodiment, this invention provides a pharmaceutical product ofthe compound of this invention. In another embodiment, this inventionprovides a tautomer of the compound of this invention. In anotherembodiment, this invention provides a hydrate of the compound of thisinvention. In another embodiment, this invention provides an N-oxide ofthe compound of this invention. In another embodiment, this inventionprovides a polymorph of the compound of this invention. In anotherembodiment, this invention provides a crystal of the compound of thisinvention. In another embodiment, this invention provides compositioncomprising a compound of this invention, as described herein, or, inanother embodiment, a combination of an isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, tautomer,hydrate, N-oxide, polymorph, or crystal of the compound of thisinvention.

In one embodiment, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like.

In one embodiment, the compounds of this invention are the pure(E)-isomers. In another embodiment, the compounds of this invention arethe pure (Z)-isomers. In another embodiment, the compounds of thisinvention are a mixture of the (E) and the (Z) isomers. In oneembodiment, the compounds of this invention are the pure (R)-isomers. Inanother embodiment, the compounds of this invention are the pure(S)-isomers. In another embodiment, the compounds of this invention area mixture of the (R) and the (S) isomers.

The compounds of the present invention can also be present in the formof a racemic mixture, containing substantially equivalent amounts ofstereoisomers. In another embodiment, the compounds of the presentinvention can be prepared or otherwise isolated, using known procedures,to obtain a stereoisomer substantially free of its correspondingstereoisomer (i.e., substantially pure). By substantially pure, it isintended that a stereoisomer is at least about 95% pure, more preferablyat least about 98% pure, most preferably at least about 99% pure.

Compounds of the present invention can also be in the form of a hydrate,which means that the compound further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

Compounds of the present invention may exist in the form of one or moreof the possible tautomers and depending on the particular conditions itmay be possible to separate some or all of the tautomers into individualand distinct entities. It is to be understood that all of the possibletautomers, including all additional enol and keto tautomers and/orisomers are hereby covered. For example the following tautomers, but notlimited to these, are included.

Tautomerization of the Imidazole Ring

The tautomers of this invention are freely interconverting tautomers,not unresolved mixtures. The imidazoles and other ring systems of thisinvention are tautomerizable. All tautomers are considered as part ofthe invention. Non limiting examples of tautomers of this invention are(5-methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(4-methyl-5-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70j);(5-ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone and(4-ethyl-5-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70k);(4-phenyl-5-propyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-phenyl-4-propyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70l); phenyl-(4-phenyl-1H-imidazol-2-yl)methanone andphenyl-(5-phenyl-1H-imidazol-2-yl)methanone (70aa);(4-fluorophenyl)(4-(4-fluorophenyl)-1H-imidazol-2-yl)methanone and(4-fluorophenyl)(5-(4-fluorophenyl)-1H-imidazol-2-yl)methanone (70r);(4-chlorophenyl)(4-(4-chlorophenyl)-1H-imidazol-2-yl)methanone and(4-chlorophenyl)(5-(4-chlorophenyl)-1H-imidazol-2-yl)methanone (70s);4-bromophenyl-(4-(4-bromophenyl)-1H-imidazol-2-yl)ketone and4-bromophenyl-(5-(4-bromophenyl)-1H-imidazol-2-yl)methanone (70t);p-tolyl(4-p-tolyl-1H-imidazol-2-yl)methanone andp-tolyl(5-p-tolyl-1H-imidazol-2-yl)methanone (70v);(4-(trifluoromethyl)phenyl)(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)methanoneand(4-(trifluoromethyl)phenyl)(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)methanone(70u); (4-methoxyphenyl)(4-(4-methoxyphenyl)-1H-imidazol-2-yl)methanoneand (4-methoxyphenyl)(5-(4-methoxyphenyl)-1H-imidazol-2-yl)methanone(70w);(4-(dimethylamino)phenyl)(4-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)methanoneand(4-(dimethylamino)phenyl)(5-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)methanone(70hh); 5-methyl-4-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole and4-methyl-5-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102b);5-ethyl-4-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole and4-ethyl-5-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102c);4-phenyl-5-propyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole and5-phenyl-4-propyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102d);3,4,5-trimethoxyphenyl-(4-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanoneand3,4,5-trimethoxyphenyl-(5-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone(70q); (4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone and(5-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone (70a);(4-(4-fluorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-fluorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70b);(4-(4-bromophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-bromophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70d); 4-bromophenyl(4-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone and4-bromophenyl(5-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone(70z).

The invention includes “pharmaceutically acceptable salts” of thecompounds of this invention, which may be produced, by reaction of acompound of this invention with an acid or base. Certain compounds,particularly those possessing acid or basic groups, can also be in theform of a salt, preferably a pharmaceutically acceptable salt. The term“pharmaceutically acceptable salt” refers to those salts that retain thebiological effectiveness and properties of the free bases or free acids,which are not biologically or otherwise undesirable. The salts areformed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like, and organicacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcysteine and the like. Other salts are known tothose of skill in the art and can readily be adapted for use inaccordance with the present invention.

Suitable pharmaceutically-acceptable salts of amines of compounds thecompounds of this invention may be prepared from an inorganic acid orfrom an organic acid. In one embodiment, examples of inorganic salts ofamines are bisulfates, borates, bromides, chlorides, hemisulfates,hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates(hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates,persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonicacids (alkylsulfonates, arylsulfonates, halogen substitutedalkylsulfonates, halogen substituted arylsulfonates), sulfonates andthiocyanates.

In one embodiment, examples of organic salts of amines may be selectedfrom aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilates,algenates, alkane carboxylates, substituted alkane carboxylates,alginates, benzenesulfonates, benzoates, bisulfates, butyrates,bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates,cyclohexylsulfamates, cyclopentanepropionates, calcium edetates,camsylates, carbonates, clavulanates, cinnamates, dicarboxylates,digluconates, dodecylsulfonates, dihydrochlorides, decanoates,enanthuates, ethanesulfonates, edetates, edisylates, estolates,esylates, fumarates, formates, fluorides, galacturonates gluconates,glutamates, glycolates, glucorate, glucoheptanoates, glycerophosphates,gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates,hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates,hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates,lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates,napsylates, N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, phenylacetate, pectinates, phenylpropionates, palmitates,pantothenates, polygalacturates, pyruvates, quinates, salicylates,succinates, stearates, sulfanilate, subacetates, tartrates,theophyllineacetates, p-toluenesulfonates (tosylates),trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates,triethiodide, tricarboxylates, undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orhydroxyls may be selected from ammonium, alkali metals to includelithium, sodium, potassium, cesium; alkaline earth metals to includecalcium, magnesium, aluminium; zinc, barium, cholines, quaternaryammoniums.

In another embodiment, examples of organic salts of carboxylic acids orhydroxyl may be selected from arginine, organic amines to includealiphatic organic amines, alicyclic organic amines, aromatic organicamines, benzathines, t-butylamines, benethamines(N-benzylphenethylamine), dicyclohexylamines, dimethylamines,diethanolamines, ethanolamines, ethylenediamines, hydrabamines,imidazoles, lysines, methylamines, meglamines, N-methyl-D-glucamines,N,N′-dibenzylethylenediamines, nicotinamides, organic amines,ornithines, pyridines, picolies, piperazines, procain,tris(hydroxymethyl)methylamines, triethylamines, triethanolamines,trimethylamines, tromethamines and ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In some embodiments, this invention provides a process for thepreparation of the compounds of this invention. In one embodiment, thearyl-imidazole is prepared by reacting an appropriately substitutedbenzaldehyde with ethylenediamine to construct the imidazoline ring,followed by oxidation of the imidazoline by an oxidizing agent to thecorresponding imidazole. In another embodiment the oxidizing agent isdiacetoxyiodobenzene, bromotrichloromethane and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), carbon-O₂ system orpalladium-carbon system. In another embodiment, the aryl-imidazole isprepared by reacting an appropriately substituted benzaldehyde withethylene diamine in the presence of iodine and potassium carbonate inorder to construct the imidazoline ring, followed by oxidation of theimidazoline ring catalyzed by diacetoxyiodobenzene,bromotrichloromethane and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),carbon-O₂ system or palladium-carbon system to the correspondingimidazole. In another embodiment, the aryl-imidazole is prepared byreacting an appropriately substituted benzaldehyde with ethylene diaminein the presence of iodine and potassium carbonate in order to constructthe imidazoline ring, followed by oxidation of the imidazoline ringcatalyzed by diacetoxyiodobenzene to the corresponding imidazole. Inanother embodiment, the aryl-imidazole is prepared by reacting anappropriately substituted benzaldehyde with ethylene diamine in thepresence of iodine and potassium carbonate in order to construct theimidazoline ring, followed by oxidation of the imidazoline ringcatalyzed by bromotrichloromethane and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to the corresponding imidazole.In one embodiment, the aryl-imidazole is prepared by reacting theappropriate benzaldehyde in ethanol with oxalaldehyde and ammoniahydroxide to construct the imidazole ring system.

In one embodiment an aryl-benzoyl-imidazole compound of this inventionis prepared by protecting the aryl-imidazole followed by coupling withan appropriately substituted benzoyl chloride, followed by removing theprotecting group. In another embodiment, the protecting group is aphenyl sulfonyl group, phthalimide, di-tert-butyl dicarbonate (Boc),fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), ormonomethoxytrityl (MMT). In another embodiment, the aryl-imidazole isprotected with phenyl sulfonyl to yield the N-sulfonyl protectedaryl-imidazole. In another embodiment, the protected aryl-imidazolecompound is prepared by reacting the aryl-imidazole with phenylsulfonylchloride and sodium hydride in THF. In another embodiment, the protectedaryl-imidazole is prepared according to FIGS. 7 and 8.

In one embodiment, the protected aryl-imidazole is coupled with anappropriately substituted benzoyl chloride to obtain a protectedaryl-benzoyl imidazole. In another embodiment, aryl-imidazole is coupledwith an appropriately substituted benzoyl chloride in the presence oftert-butyl lithium to obtain aryl-phenylsulfonyl(2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone. In anotherembodiment, the (2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone isprepared according to FIGS. 7 and 8 steps e and c, respectively.

In one embodiment, an aryl-benzoyl-imidazole is prepared by removing theprotecting group of the aryl-benzoyl-imidazole. In another embodiment,the removal of the protecting group depends on the protecting group usedand can be removed by known conditions which are known in the art. Inanother embodiment, the phenyl sulfonyl protecting group is removed bytetrabutylammonium fluoride in THF. In another embodiment,phenylsulfonyl is removed according to FIGS. 7 and 8.

In one embodiment, compounds of formula I, Ia, II, III, V and XI areprepared according to FIG. 1. In another embodiment, compounds offormula I, Ia, II, III, V, VI, VII and XI are prepared according to FIG.2. In another embodiment, compounds of formula I, Ia, II, III, V and VIare prepared according to FIG. 3. In another embodiment, compounds offormula I, Ia, II, III, V and VI are prepared according to FIG. 4. Inanother embodiment, compounds of formula I, Ia, II, III, IV, IVa, V, VIand XI are prepared according to FIG. 5. In another embodiment,compounds of formula I, Ia, II, III, VIII and XI are prepared accordingto FIG. 6.

In one embodiment, compounds of formula XII and XVIII are preparedaccording to FIG. 9. In another embodiment, compounds of formula XII,XIII, XIV, XIVa, XV, XVI, XVII, XIX and XX are prepared according toFIG. 10. In another embodiment, compounds of formula XIVa and XIX areprepared according to FIG. 11. In another embodiment, compounds offormula I, Ia, IV, IVa, XI, XXI, XXIa and XXII are prepared according toFIG. 12. In another embodiment, compounds of formula I, Ia, IV, IVa, XI,XIb, XXI, XXIa and XXII are prepared according to FIG. 13. In anotherembodiment, compounds of formula I, Ia, II, III, V, XI, XII, XIII, XIV,XV, XVII, XIX and XX are prepared according to FIG. 14. In anotherembodiment, compounds of formula I, Ia, II, IV, IVa, XI and XIc, areprepared according to FIG. 15.

In one embodiment, compounds of formula IX and IXa are preparedaccording to FIG. 16.

Pharmaceutical Composition

Another aspect of the present invention relates to a pharmaceuticalcomposition including a pharmaceutically acceptable carrier and acompound according to the aspects of the present invention. Thepharmaceutical composition can contain one or more of theabove-identified compounds of the present invention. Typically, thepharmaceutical composition of the present invention will include acompound of the present invention or its pharmaceutically acceptablesalt, as well as a pharmaceutically acceptable carrier. The term“pharmaceutically acceptable carrier” refers to any suitable adjuvants,carriers, excipients, or stabilizers, and can be in solid or liquid formsuch as, tablets, capsules, powders, solutions, suspensions, oremulsions.

Typically, the composition will contain from about 0.01 to 99 percent,preferably from about 20 to 75 percent of active compound(s), togetherwith the adjuvants, carriers and/or excipients. While individual needsmay vary, determination of optimal ranges of effective amounts of eachcomponent is within the skill of the art. Typical dosages comprise about0.01 to about 100 mg/kg body wt. The preferred dosages comprise about0.1 to about 100 mg/kg body wt. The most preferred dosages compriseabout 1 to about 100 mg/kg body wt. Treatment regimen for theadministration of the compounds of the present invention can also bedetermined readily by those with ordinary skill in art. That is, thefrequency of administration and size of the dose can be established byroutine optimization, preferably while minimizing any side effects.

The solid unit dosage forms can be of the conventional type. The solidform can be a capsule and the like, such as an ordinary gelatin typecontaining the compounds of the present invention and a carrier, forexample, lubricants and inert fillers such as, lactose, sucrose, orcornstarch. In another embodiment, these compounds are tabulated withconventional tablet bases such as lactose, sucrose, or cornstarch incombination with binders like acacia, cornstarch, or gelatin,disintegrating agents, such as cornstarch, potato starch, or alginicacid, and a lubricant, like stearic acid or magnesium stearate.

The tablets, capsules, and the like can also contain a binder such asgum tragacanth, acacia, corn starch, or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid; a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose, or saccharin. When the dosageunit form is a capsule, it can contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets can be coatedwith shellac, sugar, or both. A syrup can contain, in addition to activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye, and flavoring such as cherry or orange flavor.

For oral therapeutic administration, these active compounds can beincorporated with excipients and used in the form of tablets, capsules,elixirs, suspensions, syrups, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compound in these compositions can, of course, bevaried and can conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions according to the present inventionare prepared so that an oral dosage unit contains between about 1 mg and800 mg of active compound.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent, or with an assimilableedible carrier, or they can be enclosed in hard or soft shell capsules,or they can be compressed into tablets, or they can be incorporateddirectly with the food of the diet.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form should be sterile and should befluid to the extent that easy syringability exists. It should be stableunder the conditions of manufacture and storage and should be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi. The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol, andliquid polyethylene glycol), suitable mixtures thereof, and vegetableoils.

The compounds or pharmaceutical compositions of the present inventionmay also be administered in injectable dosages by solution or suspensionof these materials in a physiologically acceptable diluent with apharmaceutical adjuvant, carrier or excipient. Such adjuvants, carriersand/or excipients include, but are not limited to, sterile liquids, suchas water and oils, with or without the addition of a surfactant andother pharmaceutically and physiologically acceptable components.Illustrative oils are those of petroleum, animal, vegetable, orsynthetic origin, for example, peanut oil, soybean oil, or mineral oil.In general, water, saline, aqueous dextrose and related sugar solution,and glycols, such as propylene glycol or polyethylene glycol, arepreferred liquid carriers, particularly for injectable solutions.

These active compounds may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Illustrative oils are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, or mineral oil. In general, water, saline, aqueousdextrose and related sugar solution, and glycols such as, propyleneglycol or polyethylene glycol, are preferred liquid carriers,particularly for injectable solutions. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

For use as aerosols, the compounds of the present invention in solutionor suspension may be packaged in a pressurized aerosol containertogether with suitable propellants, for example, hydrocarbon propellantslike propane, butane, or isobutane with conventional adjuvants. Thematerials of the present invention also may be administered in anon-pressurized form such as in a nebulizer or atomizer.

In one embodiment, the compounds of this invention are administered incombination with an anti-cancer agent. In one embodiment, theanti-cancer agent is a monoclonal antibody. In some embodiments, themonoclonal antibodies are used for diagnosis, monitoring, or treatmentof cancer. In one embodiment, monoclonal antibodies react againstspecific antigens on cancer cells. In one embodiment, the monoclonalantibody acts as a cancer cell receptor antagonist. In one embodiment,monoclonal antibodies enhance the patient's immune response. In oneembodiment, monoclonal antibodies act against cell growth factors, thusblocking cancer cell growth. In one embodiment, anti-cancer monoclonalantibodies are conjugated or linked to anti-cancer drugs, radioisotopes,other biologic response modifiers, other toxins, or a combinationthereof. In one embodiment, anti-cancer monoclonal antibodies areconjugated or linked to a compound of this invention as describedhereinabove.

Yet another aspect of the present invention relates to a method oftreating cancer that includes selecting a subject in need of treatmentfor cancer, and administering to the subject a pharmaceuticalcomposition comprising a compound according to the first aspect of thepresent invention and a pharmaceutically acceptable carrier underconditions effective to treat cancer.

When administering the compounds of the present invention, they can beadministered systemically or, alternatively, they can be administereddirectly to a specific site where cancer cells or precancerous cells arepresent. Thus, administering can be accomplished in any manner effectivefor delivering the compounds or the pharmaceutical compositions to thecancer cells or precancerous cells. Exemplary modes of administrationinclude, without limitation, administering the compounds or compositionsorally, topically, transdermally, parenterally, subcutaneously,intravenously, intramuscularly, intraperitoneally, by intranasalinstillation, by intracavitary or intravesical instillation,intraocularly, intraarterially, intralesionally, or by application tomucous membranes, such as, that of the nose, throat, and bronchialtubes.

Biological Activity

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention. In one embodiment, use of a compound of thisinvention or a composition comprising the same, will have utility ininhibiting, suppressing, enhancing or stimulating a desired response ina subject, as will be understood by one skilled in the art. In anotherembodiment, the compositions may further comprise additional activeingredients, whose activity is useful for the particular application forwhich the compound of this invention is being administered.

In one embodiment, this invention is directed to a method of treating,suppressing, reducing the severity, reducing the risk of developing orinhibiting cancer comprising administering a compound of this inventionto a subject suffering from cancer under conditions effective to treatthe cancer.

Drug resistance is the major cause of cancer chemotherapy failure. Onemajor contributor to multidrug resistance is overexpression ofP-glycoprotein (P-gp). This protein is a clinically importanttransporter protein belonging to the ATP-binding cassette family of cellmembrane transporters. It can pump substrates including anticancer drugsout of tumor cells through an ATP-dependent mechanism.

In one embodiment, this invention provides methods for: a) treating,suppressing, reducing the severity, reducing the risk, or inhibitingdrug resistant tumors; b) treating, suppressing, reducing the severity,reducing the risk, or inhibiting metastatic cancer; c) treating,suppressing, reducing the severity, reducing the risk, or inhibitingdrug resistant cancer; d) treating, suppressing, reducing the severity,reducing the risk, or inhibiting a drug resistant cancer wherein thecancer is melanoma; e) a method of treating, suppressing, reducing theseverity, reducing the risk, or inhibiting a drug resistant cancerwherein the cancer is prostate cancer; f) a method of treating,suppressing, reducing the severity, reducing the risk, or inhibitingmetastatic melanoma; g) a method of treating, suppressing, reducing theseverity, reducing the risk, or inhibiting prostate cancer; h) treating,suppressing, reducing the severity, reducing the risk, or inhibitingcancer in a subject, wherein the subject has been previously treatedwith chemotherapy, radiotherapy, or biological therapy; comprising thestep of administering to said subject a compound of this inventionand/or an isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, orcrystal of said compound, or any combination thereof.

The compounds of the present invention are useful in the treatment,reducing the severity, reducing the risk, or inhibition of cancer,metastatic cancer, drug resistant tumors, drug resistant cancer andvarious forms of cancer. In a preferred embodiment the cancer isprostate cancer, breast cancer, ovarian cancer, skin cancer (e.g.,melanoma), lung cancer, colon cancer, leukemia, lymphoma, head and neck,pancreatic, esophageal, renal cancer or CNS cancer (e.g., glioma,glioblastoma). Treatment of these different cancers is supported by theExamples herein. Moreover, based upon their believed mode of action astubulin inhibitors, it is believed that other forms of cancer willlikewise be treatable or preventable upon administration of thecompounds or compositions of the present invention to a patient.Preferred compounds of the present invention are selectively disruptiveto cancer cells, causing ablation of cancer cells but preferably notnormal cells. Significantly, harm to normal cells is minimized becausethe cancer cells are susceptible to disruption at much lowerconcentrations of the compounds of the present invention.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting cancer in asubject. In another embodiment, the cancer is adrenocortical carcinoma,anal cancer, bladder cancer, brain tumor, brain stem tumor, breastcancer, glioma, cerebellar astrocytoma, cerebral astrocytoma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermal,pineal tumors, hypothalamic glioma, breast cancer, carcinoid tumor,carcinoma, cervical cancer, colon cancer, central nervous system (CNS)cancer, endometrial cancer, esophageal cancer, extrahepatic bile ductcancer, Ewing's family of tumors (Pnet), extracranial germ cell tumor,eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer,germ cell tumor, extragonadal, gestational trophoblastic tumor, head andneck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngealcancer, leukemia, acute lymphoblastic, leukemia, oral cavity cancer,liver cancer, lung cancer, non-small cell lung cancer, small cell,lymphoma, AIDS-related lymphoma, central nervous system (primary),lymphoma, cutaneous T-cell, lymphoma, Hodgkin's disease, non-Hodgkin'sdisease, malignant mesothelioma, melanoma, Merkel cell carcinoma,metasatic squamous carcinoma, multiple myeloma, plasma cell neoplasms,mycosis fungoides, myelodysplastic syndrome, myeloproliferativedisorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer,osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germcell tumor, ovarian low malignant potential tumor, pancreatic cancer,exocrine, pancreatic cancer, islet cell carcinoma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytomacancer, pituitary cancer, plasma cell neoplasm, prostate cancer,rhabdomyosarcoma, rectal cancer, renal cancer, renal cell cancer,salivary gland cancer, Sezary syndrome, skin cancer, cutaneous T-celllymphoma, skin cancer, Kaposi's sarcoma, skin cancer, melanoma, smallintestine cancer, soft tissue sarcoma, soft tissue sarcoma, testicularcancer, thymoma, malignant, thyroid cancer, urethral cancer, uterinecancer, sarcoma, unusual cancer of childhood, vaginal cancer, vulvarcancer, Wilms' tumor, or any combination thereof. In another embodimentthe subject has been previously treated with chemotherapy, radiotherapyor biological therapy.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a metastaticcancer in a subject. In another embodiment, the cancer is adrenocorticalcarcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor,breast cancer, glioma, cerebellar astrocytoma, cerebral astrocytoma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermal,pineal tumors, hypothalamic glioma, breast cancer, carcinoid tumor,carcinoma, cervical cancer, colon cancer, central nervous system (CNS)cancer, endometrial cancer, esophageal cancer, extrahepatic bile ductcancer, Ewing's family of tumors (Pnet), extracranial germ cell tumor,eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer,germ cell tumor, extragonadal, gestational trophoblastic tumor, head andneck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngealcancer, leukemia, acute lymphoblastic, leukemia, oral cavity cancer,liver cancer, lung cancer, non-small cell lung cancer, small cell,lymphoma, AIDS-related lymphoma, central nervous system (primary),lymphoma, cutaneous T-cell, lymphoma, Hodgkin's disease, non-Hodgkin'sdisease, malignant mesothelioma, melanoma, Merkel cell carcinoma,metasatic squamous carcinoma, multiple myeloma, plasma cell neoplasms,mycosis fungoides, myelodysplastic syndrome, myeloproliferativedisorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer,osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germcell tumor, ovarian low malignant potential tumor, pancreatic cancer,exocrine, pancreatic cancer, islet cell carcinoma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytomacancer, pituitary cancer, plasma cell neoplasm, prostate cancer,rhabdomyosarcoma, rectal cancer, renal cancer, renal cell cancer,salivary gland cancer, Sezary syndrome, skin cancer, cutaneous T-celllymphoma, skin cancer, Kaposi's sarcoma, skin cancer, melanoma, smallintestine cancer, soft tissue sarcoma, soft tissue sarcoma, testicularcancer, thymoma, malignant, thyroid cancer, urethral cancer, uterinecancer, sarcoma, unusual cancer of childhood, vaginal cancer, vulvarcancer, Wilms' tumor, or any combination thereof.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a drug-resistantcancer or resistant cancer in a subject. In another embodiment, thecancer is adrenocortical carcinoma, anal cancer, bladder cancer, braintumor, brain stem tumor, breast cancer, glioma, cerebellar astrocytoma,cerebral astrocytoma, ependymoma, medulloblastoma, supratentorialprimitive neuroectodermal, pineal tumors, hypothalamic glioma, breastcancer, carcinoid tumor, carcinoma, cervical cancer, colon cancer,central nervous system (CNS) cancer, endometrial cancer, esophagealcancer, extrahepatic bile duct cancer, Ewing's family of tumors (Pnet),extracranial germ cell tumor, eye cancer, intraocular melanoma,gallbladder cancer, gastric cancer, germ cell tumor, extragonadal,gestational trophoblastic tumor, head and neck cancer, hypopharyngealcancer, islet cell carcinoma, laryngeal cancer, leukemia, acutelymphoblastic, leukemia, oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell, lymphoma, AIDS-related lymphoma,central nervous system (primary), lymphoma, cutaneous T-cell, lymphoma,Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma,melanoma, Merkel cell carcinoma, metasatic squamous carcinoma, multiplemyeloma, plasma cell neoplasms, mycosis fungoides, myelodysplasticsyndrome, myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, exocrine, pancreaticcancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitarycancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectalcancer, renal cancer, renal cell cancer, salivary gland cancer, Sezarysyndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi'ssarcoma, skin cancer, melanoma, small intestine cancer, soft tissuesarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant,thyroid cancer, urethral cancer, uterine cancer, sarcoma, unusual cancerof childhood, vaginal cancer, vulvar cancer, Wilms' tumor, or anycombination thereof.

In one embodiment “metastatic cancer” refers to a cancer that spread(metastasized) from its original site to another area of the body.Virtually all cancers have the potential to spread. Whether metastasesdevelop depends on the complex interaction of many tumor cell factors,including the type of cancer, the degree of maturity (differentiation)of the tumor cells, the location and how long the cancer has beenpresent, as well as other incompletely understood factors. Metastasesspread in three ways—by local extension from the tumor to thesurrounding tissues, through the bloodstream to distant sites or throughthe lymphatic system to neighboring or distant lymph nodes. Each kind ofcancer may have a typical route of spread. The tumor is called by theprimary site (ex. breast cancer that has spread to the brain is calledmetastatic breast cancer to the brain).

In one embodiment “drug-resistant cancer” refers to cancer cells thatacquire resistance to chemotherapy. Cancer cells can acquire resistanceto chemotherapy by a range of mechanisms, including the mutation oroverexpression of the drug target, inactivation of the drug, orelimination of the drug from the cell. Tumors that recur after aninitial response to chemotherapy may be resistant to multiple drugs(they are multidrug resistant). In the conventional view of drugresistance, one or several cells in the tumor population acquire geneticchanges that confer drug resistance. Accordingly, the reasons for drugresistance, inter alia, are: a) some of the cells that are not killed bythe chemotherapy mutate (change) and become resistant to the drug. Oncethey multiply, there may be more resistant cells than cells that aresensitive to the chemotherapy; b) Gene amplification. A cancer cell mayproduce hundreds of copies of a particular gene. This gene triggers anoverproduction of protein that renders the anticancer drug ineffective;c) cancer cells may pump the drug out of the cell as fast as it is goingin using a molecule called p-glycoprotein; d) cancer cells may stoptaking in the drugs because the protein that transports the drug acrossthe cell wall stops working; e) the cancer cells may learn how to repairthe DNA breaks caused by some anti-cancer drugs; f) cancer cells maydevelop a mechanism that inactivates the drug. One major contributor tomultidrug resistance is overexpression of P-glycoprotein (P-gp). Thisprotein is a clinically important transporter protein belonging to theATP-binding cassette family of cell membrane transporters. It can pumpsubstrates including anticancer drugs out of tumor cells through anATP-dependent mechanism. Thus, the resistance to anticancer agents usedin chemotherapy is the main cause of treatment failure in malignantdisorders, provoking tumors to become resistant. Drug resistance is themajor cause of cancer chemotherapy failure.

In one embodiment “resistant cancer” refers to drug-resistant cancer asdescribed herein above. In another embodiment “resistant cancer” refersto cancer cells that acquire resistance to any treatment such aschemotherapy, radiotherapy or biological therapy.

In one embodiment, this invention is directed to treating, suppressing,reducing the severity, reducing the risk, or inhibiting cancer in asubject, wherein the subject has been previously treated withchemotherapy, radiotherapy or biological therapy.

In one embodiment “Chemotherapy” refers to chemical treatment for cancersuch as drugs that kill cancer cells directly. Such drugs are referredas “anti-cancer” drugs or “antineoplastics.” Today's therapy uses morethan 100 drugs to treat cancer. To cure a specific cancer. Chemotherapyis used to control tumor growth when cure is not possible; to shrinktumors before surgery or radiation therapy; to relieve symptoms (such aspain); and to destroy microscopic cancer cells that may be present afterthe known tumor is removed by surgery (called adjuvant therapy).Adjuvant therapy is given to prevent a possible cancer reoccurrence.

In one embodiment, “Radiotherapy” refers to high energy x-rays andsimilar rays (such as electrons) to treat disease. Many people withcancer will have radiotherapy as part of their treatment. This can begiven either as external radiotherapy from outside the body using x-raysor from within the body as internal radiotherapy. Radiotherapy works bydestroying the cancer cells in the treated area. Although normal cellscan also be damaged by the radiotherapy, they can usually repairthemselves. Radiotherapy treatment can cure some cancers and can alsoreduce the chance of a cancer coming back after surgery. It may be usedto reduce cancer symptoms.

In one embodiment “Biological therapy” refers to substances that occurnaturally in the body to destroy cancer cells. There are several typesof treatment including: monoclonal antibodies, cancer growth inhibitors,vaccines and gene therapy. Biological therapy is also known asimmunotherapy.

In one embodiment, this invention provides a method of treating asubject suffering from prostate cancer, metastatic prostate cancer,resistant prostate cancer or drug-resistant prostate cancer comprisingthe step of administering to said subject a compound of this invention,or its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, crystalor any combination thereof, or a composition comprising the same in anamount effective to treat prostate cancer in the subject. In anotherembodiment, the compound is compound 12db. In another embodiment, thecompound is compound 11cb. In another embodiment, the compound iscompound 11fb. In another embodiment, the compound is compound 12da. Inanother embodiment, the compound is compound 12fa. In anotherembodiment, the compound is compound 12fb. In another embodiment, thecompound is compound 12cb. In another embodiment, the compound iscompound 55. In another embodiment, the compound is compound 6b. Inanother embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

In one embodiment, this invention provides a method for suppressing,reducing the severity, reducing the risk, delaying the progression, orinhibiting prostate cancer, metastatic prostate cancer, resistantprostate cancer or drug-resistant prostate cancer in a subject,comprising administering to the subject a compound of this inventionand/or its isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, tautomer, hydrate, N-oxide, polymorph, crystalor any combination thereof or a composition comprising the same. Inanother embodiment, the compound is compound 12db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

In one embodiment, this invention provides a method of treating asubject suffering from breast cancer, metastatic breast cancer,resistant breast cancer or drug-resistant breast cancer comprising thestep of administering to said subject a compound of this invention, orits isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, tautomer, hydrate, N-oxide, polymorph, crystal or anycombination thereof, or a composition comprising the same. In anotherembodiment, the subject is a male or female. In another embodiment, thecompound is compound 12db. In another embodiment, the compound iscompound 11cb. In another embodiment, the compound is compound 11fb. Inanother embodiment, the compound is compound 12da. In anotherembodiment, the compound is compound 12fa. In another embodiment, thecompound is compound 12fb. In another embodiment, the compound iscompound 12cb. In another embodiment, the compound is compound 55. Inanother embodiment, the compound is compound 6b. In another embodiment,the compound is compound 17ya. In another embodiment, the compound iscompound 12q. In another embodiment, the compound is compound 70a. Inanother embodiment, the compound is compound 70d. In another embodiment,the compound is compound 70f. In another embodiment, the compound iscompound 70m.

In one embodiment, this invention provides a method of suppressing,reducing the severity, reducing the risk, delaying the progression, orinhibiting breast cancer, metastatic breast cancer, resistant breastcancer or drug-resistant breast cancer in a subject comprising the stepof administering to said subject a compound of this invention or itsisomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, tautomer, hydrate, N-oxide, polymorph, crystal or anycombination thereof, or a composition comprising the same. In anotherembodiment, the subject is a male or female. In another embodiment, thecompound is compound 12db. In another embodiment, the compound iscompound 11cb. In another embodiment, the compound is compound 11fb. Inanother embodiment, the compound is compound 12da. In anotherembodiment, the compound is compound 12fa. In another embodiment, thecompound is compound 12fb. In another embodiment, the compound iscompound 12cb. In another embodiment, the compound is compound 55. Inanother embodiment, the compound is compound 6b. In another embodiment,the compound is compound 17ya.

In another embodiment, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, hydrate, N-oxide,polymorph, crystal or any combination thereof, for treating,suppressing, reducing the severity, reducing the risk, delaying theprogression, or inhibiting ovarian cancer, metastatic ovarian cancer,resistant ovarian cancer or drug-resistant ovarian cancer in a subject.In another embodiment, the compound is compound 12db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

In one embodiment, this invention provides a method for treating,suppressing, reducing the severity, reducing the risk or inhibitingmelanoma, metastatic melanoma, resistant melanoma or drug-resistantmelanoma in a subject, comprising administering to the subject acompound of this invention and/or its isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, tautomer,hydrate, N-oxide, polymorph, crystal or any combination thereof. Inanother embodiment, the compound is compound 12db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal or any combination thereof, for treating, suppressing, reducingthe severity, reducing the risk, delaying the progression, or inhibitinglung cancer, metastatic lung cancer, resistant lung cancer ordrug-resistant lung cancer. In another embodiment, the compound iscompound 12db. In another embodiment, the compound is compound 11cb. Inanother embodiment, the compound is compound 11fb. In anotherembodiment, the compound is compound 12da. In another embodiment, thecompound is compound 12fa. In another embodiment, the compound iscompound 12fb. In another embodiment, the compound is compound 12cb. Inanother embodiment, the compound is compound 55. In another embodiment,the compound is compound 6b. In another embodiment, the compound iscompound 17ya. In another embodiment, the compound is compound 12q. Inanother embodiment, the compound is compound 70a. In another embodiment,the compound is compound 70d. In another embodiment, the compound iscompound 70f. In another embodiment, the compound is compound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingnon-small cell lung cancer, metastatic small cell lung cancer, resistantsmall cell lung cancer or drug-resistant small cell lung cancer. Inanother embodiment, the compound is compound 12db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingcolon cancer, metastatic colon cancer, resistant colon cancer ordrug-resistant colon cancer. In another embodiment, the compound iscompound 12db. In another embodiment, the compound is compound 11cb. Inanother embodiment, the compound is compound 11fb. In anotherembodiment, the compound is compound 12da. In another embodiment, thecompound is compound 12fa. In another embodiment, the compound iscompound 12fb. In another embodiment, the compound is compound 12cb. Inanother embodiment, the compound is compound 55. In another embodiment,the compound is compound 6b. In another embodiment, the compound iscompound 17ya. In another embodiment, the compound is compound 12q. Inanother embodiment, the compound is compound 70a. In another embodiment,the compound is compound 70d. In another embodiment, the compound iscompound 70f. In another embodiment, the compound is compound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting ofleukemia, metastatic leukemia, resistant leukemia or drug-resistantleukemia. In another embodiment, the compound is compound 12db. Inanother embodiment, the compound is compound 11cb. In anotherembodiment, the compound is compound 11fb. In another embodiment, thecompound is compound 12da. In another embodiment, the compound iscompound 12fa. In another embodiment, the compound is compound 12fb. Inanother embodiment, the compound is compound 12cb. In anotherembodiment, the compound is compound 55. In another embodiment, thecompound is compound 6b. In another embodiment, the compound is compound17ya. In another embodiment, the compound is compound 12q. In anotherembodiment, the compound is compound 70a. In another embodiment, thecompound is compound 70d. In another embodiment, the compound iscompound 70f. In another embodiment, the compound is compound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitinglymphoma, metastatic lymphoma, lymphoma or drug-resistant lymphoma. Inanother embodiment, the compound is compound 12db. In anotherembodiment, the compound is compound 11cb. In another embodiment, thecompound is compound 11fb. In another embodiment, the compound iscompound 12da. In another embodiment, the compound is compound 12fa. Inanother embodiment, the compound is compound 12fb. In anotherembodiment, the compound is compound 12cb. In another embodiment, thecompound is compound 55. In another embodiment, the compound is compound6b. In another embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitinghead and neck cancer, metastatic head and neck cancer, resistant headand neck cancer or drug-resistant head and neck cancer. In anotherembodiment, the compound is compound 12db. In another embodiment, thecompound is compound 11cb. In another embodiment, the compound iscompound 11fb. In another embodiment, the compound is compound 12da. Inanother embodiment, the compound is compound 12fa. In anotherembodiment, the compound is compound 12fb. In another embodiment, thecompound is compound 12cb. In another embodiment, the compound iscompound 55. In another embodiment, the compound is compound 6b. Inanother embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting ofpancreatic cancer, metastatic pancreatic cancer, resistant pancreaticcancer or drug-resistant pancreatic cancer. In another embodiment, thecompound is compound 12db. In another embodiment, the compound iscompound 11cb. In another embodiment, the compound is compound 11fb. Inanother embodiment, the compound is compound 12da. In anotherembodiment, the compound is compound 12fa. In another embodiment, thecompound is compound 12fb. In another embodiment, the compound iscompound 12cb. In another embodiment, the compound is compound 55. Inanother embodiment, the compound is compound 6b. In another embodiment,the compound is compound 17ya. In another embodiment, the compound iscompound 12q. In another embodiment, the compound is compound 70a. Inanother embodiment, the compound is compound 70d. In another embodiment,the compound is compound 70f. In another embodiment, the compound iscompound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingesophageal cancer, metastatic esophageal cancer, resistant esophagealcancer or drug-resistant esophageal cancer. In another embodiment, thecompound is compound 12db. In another embodiment, the compound iscompound 11cb. In another embodiment, the compound is compound 11fb. Inanother embodiment, the compound is compound 12da. In anotherembodiment, the compound is compound 12fa. In another embodiment, thecompound is compound 12fb. In another embodiment, the compound iscompound 12cb. In another embodiment, the compound is compound 55. Inanother embodiment, the compound is compound 6b. In another embodiment,the compound is compound 17ya. In another embodiment, the compound iscompound 12q. In another embodiment, the compound is compound 70a. Inanother embodiment, the compound is compound 70d. In another embodiment,the compound is compound 70f. In another embodiment, the compound iscompound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibitingrenal cancer, metastatic renal cancer, resistant renal cancer ordrug-resistant renal cancer. In another embodiment, the compound iscompound 12db. In another embodiment, the compound is compound 11cb. Inanother embodiment, the compound is compound 11fb. In anotherembodiment, the compound is compound 12da. In another embodiment, thecompound is compound 12fa. In another embodiment, the compound iscompound 12fb. In another embodiment, the compound is compound 12cb. Inanother embodiment, the compound is compound 55. In another embodiment,the compound is compound 6b. In another embodiment, the compound iscompound 17ya. In another embodiment, the compound is compound 12q. Inanother embodiment, the compound is compound 70a. In another embodiment,the compound is compound 70d. In another embodiment, the compound iscompound 70f. In another embodiment, the compound is compound 70m.

In another embodiment, this invention provides for the use of a compoundas herein described, or isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, tautomer, hydrate, N-oxide, polymorph,crystal any combination thereof, for treating, suppressing, reducing theseverity, reducing the risk, delaying the progression, or inhibiting CNScancer, metastatic CNS cancer, resistant CNS cancer or drug-resistantCNS cancer. In another embodiment, the compound is compound 12db. Inanother embodiment, the compound is compound 11cb. In anotherembodiment, the compound is compound 11fb. In another embodiment, thecompound is compound 12da. In another embodiment, the compound iscompound 12fa. In another embodiment, the compound is compound 12fb. Inanother embodiment, the compound is compound 12cb. In anotherembodiment, the compound is compound 55. In another embodiment, thecompound is compound 6b. In another embodiment, the compound is compound17ya. In another embodiment, the compound is compound 12q. In anotherembodiment, the compound is compound 70a. In another embodiment, thecompound is compound 70d. In another embodiment, the compound iscompound 70f. In another embodiment, the compound is compound 70m.

In some embodiments, this invention provides for the use of a compoundas herein described, or its isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, tautomer, polymorph, crystal,N-oxide, hydrate or any combination thereof, for treating, suppressing,reducing the severity, reducing the risk, or inhibiting a drug resistantcancerous tumor or tumors in a subject. In another embodiment, thecancer is adrenocortical carcinoma, anal cancer, bladder cancer, braintumor, brain stem tumor, breast cancer, glioma, cerebellar astrocytoma,cerebral astrocytoma, ependymoma, medulloblastoma, supratentorialprimitive neuroectodermal, pineal tumors, hypothalamic glioma, breastcancer, carcinoid tumor, carcinoma, cervical cancer, colon cancer,central nervous system (CNS) cancer, endometrial cancer, esophagealcancer, extrahepatic bile duct cancer, Ewing's family of tumors (Pnet),extracranial germ cell tumor, eye cancer, intraocular melanoma,gallbladder cancer, gastric cancer, germ cell tumor, extragonadal,gestational trophoblastic tumor, head and neck cancer, hypopharyngealcancer, islet cell carcinoma, laryngeal cancer, leukemia, acutelymphoblastic, leukemia, oral cavity cancer, liver cancer, lung cancer,non-small cell lung cancer, small cell, lymphoma, AIDS-related lymphoma,central nervous system (primary), lymphoma, cutaneous T-cell, lymphoma,Hodgkin's disease, non-Hodgkin's disease, malignant mesothelioma,melanoma, Merkel cell carcinoma, metasatic squamous carcinoma, multiplemyeloma, plasma cell neoplasms, mycosis fungoides, myelodysplasticsyndrome, myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, exocrine, pancreaticcancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pheochromocytoma cancer, pituitarycancer, plasma cell neoplasm, prostate cancer, rhabdomyosarcoma, rectalcancer, renal cancer, renal cell cancer, salivary gland cancer, Sezarysyndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi'ssarcoma, skin cancer, melanoma, small intestine cancer, soft tissuesarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant,thyroid cancer, urethral cancer, uterine cancer, sarcoma, unusual cancerof childhood, vaginal cancer, vulvar cancer, Wilms' tumor, or anycombination thereof. In another embodiment, the compound is compound12db. In another embodiment, the compound is compound 11cb. In anotherembodiment, the compound is compound 11fb. In another embodiment, thecompound is compound 12da. In another embodiment, the compound iscompound 12fa. In another embodiment, the compound is compound 12fb. Inanother embodiment, the compound is compound 12cb. In anotherembodiment, the compound is compound 55. In another embodiment, thecompound is compound 6b. In another embodiment, the compound is compound17ya. In another embodiment, the compound is compound 12q. In anotherembodiment, the compound is compound 70a. In another embodiment, thecompound is compound 70d. In another embodiment, the compound iscompound 70f. In another embodiment, the compound is compound 70m.

In another embodiment, the tumor is prostate cancer tumor. In anotherembodiment, the tumor is ovarian cancer tumor. In another embodiment,the tumor is a melanoma tumor. In another embodiment, the tumor is amultidrug resistant (MDR) melanoma tumor.

In one embodiment, this invention is directed to a method of destroyinga cancerous cell comprising: providing a compound of this invention andcontacting the cancerous cell with the compound under conditionseffective to destroy the contacted cancerous cell. According to variousembodiments of destroying the cancerous cells, the cells to be destroyedcan be located either in vivo or ex vivo (i.e., in culture). In anotherembodiment, the compound is compound 12db. In another embodiment, thecompound is compound 11cb. In another embodiment, the compound iscompound 11fb. In another embodiment, the compound is compound 12da. Inanother embodiment, the compound is compound 12fa. In anotherembodiment, the compound is compound 12fb. In another embodiment, thecompound is compound 12cb. In another embodiment, the compound iscompound 55. In another embodiment, the compound is compound 6b. Inanother embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

In another embodiment, the cancer is selected from the group consistingof prostate cancer, breast cancer, ovarian cancer, skin cancer,melanoma, lung cancer, colon cancer, leukemia, renal cancer, CNS cancer,and combinations thereof.

A still further aspect of the present invention relates to a method oftreating or preventing a cancerous condition that includes: providing acompound of the present invention and then administering an effectiveamount of the compound to a patient in a manner effective to treat orprevent a cancerous condition.

According to one embodiment, the patient to be treated is characterizedby the presence of a precancerous condition, and the administering ofthe compound is effective to prevent development of the precancerouscondition into the cancerous condition. This can occur by destroying theprecancerous cell prior to or concurrent with its further developmentinto a cancerous state.

According to another embodiment, the patient to be treated ischaracterized by the presence of a cancerous condition, and theadministering of the compound is effective either to cause regression ofthe cancerous condition or to inhibit growth of the cancerous condition,i.e., stopping its growth altogether or reducing its rate of growth.This preferably occurs by destroying cancer cells, regardless of theirlocation in the patient body. That is, whether the cancer cells arelocated at a primary tumor site or whether the cancer cells havemetastasized and created secondary tumors within the patient body.

As used herein, subject or patient refers to any mammalian patient,including without limitation, humans and other primates, dogs, cats,horses, cows, sheep, pigs, rats, mice, and other rodents. In oneembodiment, the subject is male. In another embodiment, the subject isfemale. In some embodiments, while the methods as described herein maybe useful for treating either males or females.

When administering the compounds of the present invention, they can beadministered systemically or, alternatively, they can be administereddirectly to a specific site where cancer cells or precancerous cells arepresent. Thus, administering can be accomplished in any manner effectivefor delivering the compounds or the pharmaceutical compositions to thecancer cells or precancerous cells. Exemplary modes of administrationinclude, without limitation, administering the compounds or compositionsorally, topically, transdermally, parenterally, subcutaneously,intravenously, intramuscularly, intraperitoneally, by intranasalinstillation, by intracavitary or intravesical instillation,intraocularly, intraarterially, intralesionally, or by application tomucous membranes, such as, that of the nose, throat, and bronchialtubes.

The compounds of the present invention are useful in the treatment orprevention of various forms of cancer, particularly prostate cancer,breast cancer, ovarian, skin cancer (e.g., melanoma), lung cancer, coloncancer, leukemia, renal cancer, and CNS cancer (e.g., glioma,glioblastoma). Treatment of these different cancers is supported by theExamples herein. Moreover, based upon their believed mode of action astubulin inhibitors, it is believed that other forms of cancer willlikewise be treatable or preventable upon administration of thecompounds or compositions of the present invention to a patient.Preferred compounds of the present invention are selectively disruptiveto cancer cells, causing ablation of cancer cells but preferably notnormal cells. Significantly, harm to normal cells is minimized becausethe cancer cells are susceptible to disruption at much lowerconcentrations of the compounds of the present invention.

The compounds of the present invention are useful in the treatment,reducing the severity, reducing the risk, or inhibition of cancer,metastatic cancer, resistant cancer or drug-resistant cancer.

In another embodiment, the cancer is prostate cancer, breast cancer,ovarian, skin cancer (e.g., melanoma), lung cancer, colon cancer,leukemia, lymphoma, head and neck, pancreatic, esophageal, renal canceror CNS cancer. Treatment of these different cancers is supported by theExamples herein. Moreover, based upon their believed mode of action astubulin inhibitors, it is believed that other forms of cancer willlikewise be treatable or preventable upon administration of thecompounds or compositions of the present invention to a patient.Preferred compounds of the present invention are selectively disruptiveto cancer cells, causing ablation of cancer cells but preferably notnormal cells. Significantly, harm to normal cells is minimized becausethe cancer cells are susceptible to disruption at much lowerconcentrations of the compounds of the present invention. In anotherembodiment, the compound is compound 12db. In another embodiment, thecompound is compound 11cb. In another embodiment, the compound iscompound 11fb. In another embodiment, the compound is compound 12da. Inanother embodiment, the compound is compound 12fa. In anotherembodiment, the compound is compound 12fb. In another embodiment, thecompound is compound 12cb. In another embodiment, the compound iscompound 55. In another embodiment, the compound is compound 6b. Inanother embodiment, the compound is compound 17ya. In anotherembodiment, the compound is compound 12q. In another embodiment, thecompound is compound 70a. In another embodiment, the compound iscompound 70d. In another embodiment, the compound is compound 70f. Inanother embodiment, the compound is compound 70m.

As used herein, subject or patient refers to any mammalian patient,including without limitation, humans and other primates, dogs, cats,horses, cows, sheep, pigs, rats, mice, and other rodents. In someembodiments, while the methods as described herein may be useful fortreating either males or females.

In one embodiment, the compound is administered in combination with ananti-cancer agent by administering the compounds as herein described,alone or in combination with other agents.

When the compounds or pharmaceutical compositions of the presentinvention are administered to treat, suppress, reduce the severity,reduce the risk, or inhibit a cancerous condition, the pharmaceuticalcomposition can also contain, or can be administered in conjunctionwith, other therapeutic agents or treatment regimen presently known orhereafter developed for the treatment of various types of cancer.Examples of other therapeutic agents or treatment regimen include,without limitation, radiation therapy, immunotherapy, chemotherapy,surgical intervention, and combinations thereof.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES

The Examples set forth below are for illustrative purposes only and arenot intended to limit, in any way, the scope of the present invention.

Materials and Methods:

General.

All reagents were purchased from Sigma-Aldrich Chemical Co., FisherScientific (Pittsburgh, Pa.), AK Scientific (Mountain View, Calif.),Oakwood Products (West Columbia, S.C.), etc. and were used withoutfurther purification. Moisture-sensitive reactions were carried under anargon atmosphere. ABT-751 was prepared according methods reported byYoshino et al.²⁶ Routine thin layer chromatography (TLC) was performedon aluminum backed Uniplates (Analtech, Newark, Del.). Melting pointswere measured with Fisher-Johns melting point apparatus (uncorrected).NMR spectra were obtained on a Bruker AX 300 (Billerica, Mass.)spectrometer or Varian Inova-500 (Vernon Hills, Ill.) spectrometer.Chemical shifts are reported as parts per million (ppm) relative to TMSin CDCl₃. Mass spectral data was collected on a Bruker ESQUIREelectrospray/ion trap instrument in positive and negative ion modes.Elemental analyses were performed by Atlantic Microlab Inc.

Cell Culture and Cytotoxicity Assay of Prostate Cancer and Melanoma.

All cell lines were obtained from ATCC (American Type CultureCollection, Manassas, Va., USA), while cell culture supplies werepurchased from Cellgro Mediatech (Herndon, Va., USA). We examined theantiproliferative activity of our anti-tubulin compounds in four humanprostate cancer cell lines (LNCaP, DU 145, PC-3, and PPC-1) and twohuman melanoma cell lines (A375 and WM-164). Human ovarian cell lineOVCAR-8 and its resistant cell line that over-expresses P-gp(NCI/ADR-RES) were used as MDR models. Both ovarian cell lines wereobtained from National Cancer Institutes (NCI). All cell lines weretested and authenticated by either ATCC or NCI. All prostate cancer andovarian cancer cell lines were cultured in RPMI 1640, supplemented with10% fetal bovine serum (FBS). Melanoma cells were cultured in DMEM,supplemented with 5% FBS, 1% antibiotic/antimycotic mixture(Sigma-Aldrich, Inc., St. Louis, Mo., USA) and bovine insulin (5 μg/mL;Sigma-Aldrich). The cytotoxic potential of the anti-tubulin compoundswas evaluated using the sulforhodamine B (SRB) assay after 96 h oftreatment.

Aqueous Solubility.

The solubility of drugs was determined by Multiscreen Solubility FilterPlate (Millipore Corporate, Billerica, Mass.) coupled with LC-MS/MS.Briefly, 198 μL of phosphate buffered saline (PBS) buffer (pH 7.4) wasloaded into 96-well plate, and 2 μL of 10 mM test compounds (in DMSO)was dispensed and mixed with gentle shaking (200-300 rpm) for 1.5 h atRT (N=3). The plate was centrifuged at 800 g for 5 min, and the filtratewas used to determine its concentration and solubility of test compoundby LC-MS/MS as described below.

Pharmacokinetic Study.

Female Sprague-Dawley rats (n=3 or 4; 254±4 g) were purchased fromHarlan Inc. (Indianapolis, Ind.). Rat thoracic jugular vein catheterswere purchased from Braintree Scientific Inc. (Braintree, Mass.). Onarrival at the animal facility, the animals were acclimated for 3 daysin a temperature-controlled room (20-22° C.) with a 12 h light/darkcycle before any treatment. Compound 1h was administered intravenously(i.v.) into the jugular vein catheters at a dose of 2.5 mg/kg (inDMSO/PEG300, 2/8), whereas 5Ha and 5Hc were dosed at 5 mg/kg (inDMSO/PEG300, 1/9). An equal volume of heparinized saline was injected toreplace the removed blood, and blood samples (250 μL) were collected viathe jugular vein catheters at 10, 20, 30 min, and 1, 2, 4, 8, 12, 24 h.Compounds 1h, 5Ha and 5Hc were given (p.o.) by oral gavage at 10 mg/kg(in Tween80/DMSO/H₂O, 2/1/7). All blood samples (250 μL) after oraladministration were collected via the jugular vein catheters at 30, 60,90 min, 120 min, 150 min, 180 min, 210 min, 240 min, and 8, 12, 24 h.Heparinized syringes and vials were prepared prior to blood collection.Plasma samples were prepared by centrifuging the blood samples at 8,000g for 5 min. All plasma samples were stored immediately at −80° C. untilanalyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard((3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone). The sampleswere thoroughly mixed, centrifuged, and the organic extract wastransferred to autosampler for LC-MS/MS analysis. Multiple reactionmonitoring (MRM) mode, scanning m/z 356→188 (compound 1h), m/z 371→203(compound 5Ha), m/z 389→221 (compound 5Hc), and m/z 309→171 (theinternal standard), was used to obtain the most sensitive signals. Thepharmacokinetic parameters were determined using non-compartmentalanalysis (WinNonlin, Pharsight Corporation, Mountain View, Calif.)

Analytical Method.

Sample solution (10 μL) was injected into an Agilent series HPLC system(Agilent 1100 Series Agilent 1100 Chemstation, Agilent Technology Co,Ltd). All analytes were separated on a narrow-bore C18 column (AlltechAlltima HP, 2.1×100 mm, 3 μm, Fisher, Fair Lawn, N.J.). Two gradientmodes were used. Gradient mode was used to achieve the separation ofanalytes using mixtures of mobile phase A [ACN/H₂O (5%/95%, v/v)containing 0.1% formic acid] and mobile phase B [ACN/H₂O (95%/5%, v/v)containing 0.1% formic acid] at a flow rate of 300 μL/min. Mobile phaseA was used at 15% from 0 to 1 min followed by a linearly programmedgradient to 100% of mobile phase B within 6 min, 100% of mobile phase Bwas maintained for 0.5 min before a quick ramp to 15% mobile phase A.Mobile phase A was continued for another 12 min towards the end ofanalysis.

In Vitro Tubulin Polymerization Assay.

Bovine brain tubulin (0.4 mg, >97% pure) (Cytoskeleton, Denver, Colo.)was mixed with 10 μM of the test compounds and incubated in 100 μL ofgeneral tubulin buffer (80 mM PIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, and 1 mMGTP) at pH 6.9. The absorbance of wavelength at 340 nm was monitoredevery 1 min for 20 min by the SYNERGY 4 Microplate Reader (Bio-TekInstruments, Winooski, Vt.). The spectrophotometer was set at 37° C. fortubulin polymerization.

A triple-quadruple mass spectrometer, API Qtrap 4000™ (AppliedBiosystems/MDS SCIEX, Concord, Ontario, Canada), operating with aTurboIonSpray source was used. The spraying needle voltage was set at 5kV for positive mode. Curtain gas was set at 10; Gas 1 and gas 2 wereset 50. Collision-Assisted-Dissociation (CAD) gas at medium and thesource heater probe temperature at 500° C. Data acquisition andquantitative processing were accomplished using Analyst™ software, Ver.1.4.1 (Applied Biosystems).

The purity of the final compounds was tested via RP-HPLC on a Waters2695 HPLC system installed with a Photodiode Array Detector. Two RP-HPLCmethods were conducted using a Supelco Ascentis™ 5 μM C-18 column(250×4.6 mm) at ambient temperature, and a flow rate of 0.7 mL/min.HPLC1: Gradient: Solvent A (water) and Solvent B (methanol): 0-20 min40-100% B (linear gradient), 20-27 min 100% B. HPLC2: Gradient: SolventA (water) and Solvent B (methanol): 0-15 min 40-100% B (lineargradient), 15-25 min 100% B. UV detection at 254 nm.

The compounds of this invention were prepared according to FIGS. 1-17.

Example 1 Synthesis of B Ring Variant Compounds

B ring variant compounds were synthesized according to FIGS. 1 and 2.

Oxazole B Ring Synthesis of(2-Phenyl-oxazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone (36a) (FIG.1)

(2R)-2-Phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (32a)

Acetyl chloride (6.8 mL) was added dropwise to ice-cold methanol (30mL). After the addition of L-serine (0.48 mmol), the reaction mixturewas warmed to room temperature (RT) and stirred overnight. Evaporationof the solvent gave white solid (2R)-3-hydroxy-2-methyl-propionic acidmethyl ester HCl salt, which was used without purification in the nextstep. Triethylamine (11 mL, 72.3 mmol) was added slowly to a solution ofethyl benzimidate hydrochloride (11.6 g, 62.8 mmol) in CH₂Cl₂ (150 mL).The reaction mixture was stirred at RT for 30 min and(2R)-3-hydroxy-2-methyl-propionic acid methyl ester HCl salt (13.5 g,79.6 mmol) was added by portion. The resulting mixture was stirred for48 h and concentrated under reduced pressure. The compound 32a wasseparated from flash column as a yellow oil (12.3 g, 95.9%). ¹H NMR(CDCl₃) δ 7.99-7.38 (m, 5H), 4.97 (dd, 1H, J=7.8 Hz, J=10.5 Hz), 4.70(t, 1H, J=8.7 Hz), 4.62 (dd, 1H, J=8.7 Hz, J=10.5 Hz), 3.82 (s, 3H); MS(ESI) m/z 206.1 (M+H)⁺.

(2R)-2-Phenyl-4,5-dihydro-oxazole-4-carboxylic acid (33a)

To an ice-cooled solution of 32a in MeOH/H₂O was added LiOH (2.5 equiv)with stifling. The mixture was allowed to warm to RT in 1 h,concentrated in vacuo, and the white solid was dissolved in H₂O andacidified with 1 N HCl to pH 2.0 and extracted with MgSO₄, filtered andconcentrated in vacuo to provide the acid 33a as a white solid (95.8%).¹H NMR (CDCl₃) δ 7.98 (d, 2H), 7.57-7.42 (m, 3H), 5.04 (dd, 1H, J=7.8Hz, J=10.8 Hz), 4.80 (t, 1H, J=8.7 Hz), 4.70 (dd, 1H, J=9.0 Hz, J=10.8Hz); MS (ESI) m/z 191.9 (M+H)⁺, 189.7 (M−H)⁻, 145.8 (M-COOH)⁻.

(2R)-2-Phenyl-4,5-dihydro-oxazole-4-carboxylic acid methoxy-methyl-amide(34a)

To a mixture of 33a (5 mmol), EDCI (6 mmol), HOBt (5 mmol) and Et₃N (5mmol) in CH₂Cl₂ (50 mL) was added HNCH₃OCH₃ (5 mmol) and stiflingcontinued at RT for 6-8 h. The reaction mixture was diluted with CH₂Cl₂(100 mL) and sequentially washed with water, satd. NaHCO₃, brine anddried over MgSO₄. The solvent was removed under reduced pressure toyield a crude product 34a, which was purified by column chromatographyas a white solid (61.0%). ¹H NMR (CDCl₃) δ 7.98-7.36 (m, 5H), 7.57-7.42(m, 3H), 5.35 (br, t, 1H), 4.81 (br, t, 1H), 4.52 (dd, 1H, J=8.7 Hz,J=10.2 Hz), 3.90 (s, 3H), 3.27 (s, 3H); MS (ESI) m/z 257.0 (M+H)⁺.

(2R)-(2-Phenyl-4,5-dihydro-oxazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone(35a)

To a solution of n-BuLi (1.6 M, 0.713 mL) in 8 mL THF was added asolution of 3,4,5-trimethoxybromobenzene (1.09 mmol) in 3 mL THF under−78° C. The mixture was allowed to stir for 2 h and a solution ofWeinreb amide 34a (1.14 mmol) in 3 mL THF was charged. The temperaturewas allowed to increase at RT and stirred overnight. The reactionmixture was quenched with satd. NH₄Cl, extracted with ethyl ether, driedwith MgSO₄. The solvent was removed under reduced pressure to yield acrude product, which was purified by column chromatography to obtainpure compound 35a as a white solid (47.9%). ¹H NMR (CDCl₃) δ 7.97-7.94(m, 2H), 7.62 (s, 2H), 7.54-7.37 (m, 3H), 5.61 (q, 1H, J=7.5 Hz, 9.9Hz), 5.12 (t, 1H, J=7.5 Hz), 4.57 (q, 1H, J=7.8 Hz, 9.9 Hz), 3.96 (s,6H), 3.95 (s, 3H); MS (ESI) m/z 364.1 (M+Na)⁺, 340.1 (M−H)⁻.

(2-Phenyl-oxazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone (36a)

A mixture of 35a (1.48 mmol), CBrCl₃ (2.59 mmol) and DBU (2.97 mmol) inCH₂Cl₂ (20 mL) was stirred overnight. The reaction mixture was absorbedon silica gel and purified by column chromatography to yield pure 36a asdesired (61.6%). ¹H NMR (CDCl₃) δ 8.37 (s, 1H), 8.14-8.12 (m, 2H), 7.74(s, 2H), 7.52-7.49 (m, 3H), 3.97 (s, 9H); MS (ESI) m/z 362.1 (M+Na)⁺.

Benzene, pyrimidine, pyridine, furan, thiophene, thiazole, pyrazole andpiperidine B ring variants (FIG. 2)

B ring variants (12-1d, 1k) were obtained from their corresponding acids(37a-37d, 37k). Compound 1f with thiophene in B ring position can not beseparated from the mixture of if and a Grignard reagent couplingby-product 3,4,5,3′,4′,5′-hexamethoxybiphenyl using flash column. So analternative method was used to prepare 1f: Weinreb amide 38f wasconverted into its corresponding aldehyde which was further reacted with3,4,5-trimethoxyphenylmagnesium bromide to afford the alcohol 40f, whichcan be easily separated from 3,4,5,3′,4′,5′-hexamethoxybiphenyl usingflash column chromatography. Oxidation with pyridinium dichromate (PDC)or DMSO did not afford if from secondary alcohol 40f with good yields.But using Dess-Martin periodinane reagent as oxidant successfully formedthe desired ketone compound 1f. 1e and 1i were prepared from alcohols40e and 40i using a similar method. Compound 1g was obtained via acoupling reaction from piperidine 41g and 3,4,5-trimethoxybenzoic acid.

Benzene B Ring Synthesis ofBiphenyl-3-yl(3,4,5-trimethoxyphenyl)methanone (1a) (FIG. 2)

N-Methoxy-N-methylbiphenyl-3-carboxamide (38a)

To a mixture of 37a (5 mmol), EDCI (6 mmol), HOBt (5 mmol) and NMM (11mmol) in CH₂Cl₂ (50 mL) was added HNCH₃OCH₃HCl salt (5 mmol) andstirring continued at RT for 2 h. The reaction mixture was diluted withCH₂Cl₂ (100 mL) and sequentially washed with water, satd. NaHCO₃, brineand dried over MgSO₄. The solvent was removed under reduced pressure toyield a colorless oil, which was used for next step (58.4%). MS (ESI)m/z 264.0 (M+Na)⁺.

Biphenyl-3-yl(3,4,5-trimethoxyphenyl)methanone (1a)

To a solution of 38a (FIG. 2) (0.174 g, 0.72 mmoL) in 5 mL THF was addeda THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 1.08mmol) at 0° C. The mixture was allowed to stir for 30 min and quenchedwith satd. NH₄Cl, extracted with ethyl ether, dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was purified by column chromatography to obtain pure compound 1aas a white solid (43.8%). ¹H NMR (CDCl₃) δ 8.02 (t, 1H), 7.84-7.74 (m,2H), 7.64-7.38 (m, 6H), 7.11 (s, 2H), 3.95 (s, 3H), 3.88 (s, 6H); MS(ESI) m/z 371.1 (M+Na)⁺.

Pyrimidine B Ring Synthesis of(6-Phenylpyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone (1b) (FIG. 2)

N-Methoxy-N-methyl-6-phenylpyrimidine-4-carboxamide (38b)

To a mixture of 37b (5 mmol), EDCI (6 mmol), HOBt (5 mmol) and NMM (11mmol) in CH₂Cl₂ (50 mL) was added HNCH₃OCH₃HCl salt (5 mmol) andstifling continued at RT for overnight. The reaction mixture was dilutedwith CH₂Cl₂ (100 mL) and sequentially washed with water, satd. NaHCO₃,brine and dried over MgSO₄. The solvent was removed under reducedpressure to yield a crude product, which was purified by columnchromatography to obtain pure compound 38b as a yellow solid (62.3%). ¹HNMR (CDCl₃) δ 9.28 (s, 1H), 8.14-8.06 (m, 2H), 7.96 (br, s, 1H),7.54-7.50 (m, 3H), 5.35 (br, t, 1H), 4.81 (br, t, 1H), 4.52 (dd, 1H,J=8.7 Hz, J=10.2 Hz), 3.79 (s, 3H), 3.42 (s, 3H); MS (ESI) m/z 266.0(M+Na)⁺.

(6-Phenylpyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone (1b)

To a solution of 38b (0.243 g, 1 mmoL) in 5 mL THF was added a THFsolution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.6 mL, 1.4mmol) at 0° C. The mixture was allowed to stir for 30 min and quenchedwith satd. NH₄Cl, extracted with ethyl ether, dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was purified by column chromatography to obtain pure compound 1b(52.3%). ¹H NMR (CDCl₃) δ 9.40 (d, 1H, J=1.5 Hz), 8.29 (d, 1H, J=1.5Hz), 8.22-8.18, 7.57-7.54 (m, 5H), 7.46 (s, 2H), 3.96 (s, 3H), 3.91 (s,6H); MS (ESI) m/z 351.1 (M+H)⁺.

Pyridine B Ring Synthesis of(6-Phenylpyridin-2-yl)(3,4,5-trimethoxyphenyl)methanone (1c) (FIG. 2)

N-Methoxy-N-methyl-6-phenylpicolinamide (38c)

To a mixture of 37c (1.77 mmol), EDCI (2.12 mmol), HOBt (1.86 mmol) andNMM (3.54 mmol) in CH₂Cl₂ (20 mL) was added HNCH₃OCH₃HCl salt (1.86mmol) and stirring continued at RT for overnight. The reaction mixturewas diluted with CH₂Cl₂ (40 mL) and sequentially washed with water,satd. NaHCO₃, brine and dried over MgSO₄. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to obtain pure compound 38c as a colorless oil (51.2%).¹H NMR (CDCl₃) δ 8.02 (d, 1H, J=7.0 Hz), 7.86-7.81 (m, 2H), 7.55 (br,1H), 7.48 (t, 2H), 7.44-7.41 (m, 1H), 3.82 (s, 3H), 3.44 (s, br, 3H); MS(ESI) m/z 265.0 (M+Na)⁺.

(6-Phenylpyridin-2-yl)(3,4,5-trimethoxyphenyl)methanone (1c)

To a solution of 38c (0.210 g, 0.86 mmoL) in 5 mL THF was added a THFsolution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 3.5 mL, 1.73mmol) at 0° C. The mixture was allowed to stir for 30 min and quenchedwith water, extracted with ethyl acetate and dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was purified by column chromatography to obtain pure 1c as whiteneedle crystals (78%). ¹H NMR (CDCl₃) δ 8.10 (d, br, 2H), 8.02-8.00 (m,1H), 7.97-7.96 (m, 2H), 7.66 (s, 2H), 7.49-7.43 (m, 3H), 3.97 (s, 3H),3.89 (s, 6H); MS (ESI) m/z 372.6 (M+Na)⁺.

Furan B Ring Synthesis of(5-Phenylfuran-2-yl)(3,4,5-trimethoxyphenyl)methanone (1d) (FIG. 2)

N-Methoxy-N-methyl-5-phenylfuran-2-carboxamide (38d)

To a mixture of 37d (10 mmol), EDCI (12 mmol), HOBt (11 mmol) and NMM(21 mmol) in CH₂Cl₂ (200 mL) was added HNCH₃OCH₃HCl salt (10.5 mmol) andstifling continued at RT for overnight. The reaction mixture was dilutedwith CH₂Cl₂ (200 mL) and sequentially washed with water, satd. NaHCO₃,brine and dried over MgSO₄. The solvent was removed under reducedpressure to yield a crude product, which was purified by columnchromatography to obtain pure compound 38d. (95.2%). ¹H NMR (CDCl₃) δ7.82 (d, 1H, J=7.0 Hz), 7.46-7.43 (t, 2H), 7.37-7.34 (m, 1H), 7.25 (d,1H, J=4.0 Hz), 6.78 (d, 1H, J=4.0 Hz), 3.86 (s, 3H), 3.41 (s, 3H); MS(ESI) m/z 254.1 (M+Na)⁺.

(5-Phenylfuran-2-yl)(3,4,5-trimethoxyphenyl)methanone (1d)

To a solution of 38d (0.231 g, 1 mmoL) in 5 mL THF was added a THFsolution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 4.0 mL, 2mmol) at 0° C. The mixture was allowed to stir for 30 min and quenchedwith water, extracted with ethyl acetate and dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was purified by column chromatography to obtain pure compound 1das white crystals (35.5%). ¹H NMR (CDCl₃) δ 7.85-7.82 (m, 1H), 7.48-7.36(m, 4H), 7.35 (s, 2H), 7.25 (d, 1H, J=4.0 Hz), 6.86 (d, 1H, J=4.2 Hz),3.96 (s, 3H), 3.95 (s, 6H); MS (ESI) m/z 339.1 (M+H)⁺.

Thiazole B Ring Synthesis of(2-Phenylthiazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1e) (FIG. 2)

(2-Phenylthiazol-5-yl)(3,4,5-trimethoxyphenyl)methanol (40e)

To a solution of 2-phenylthiazole-5-carbaldehyde 38e (0.567 g, 3 mmoL)in 15 mL THF was added a THF solution of3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 6.5 mL, 3.25 mmol) at 0°C. The mixture was allowed to stir for 30 min and quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 40e (72.9%).¹H NMR (CDCl₃) δ 7.90 (m, 2H), 7.64 (s, 1H), 7.41 (m, 3H), 6.69 (s, br,2H), 6.04 (s, 1H), 3.86 (s, 6H), 3.85 (s, 3H), 1.57 (d, 1H, J=5.5 Hz);MS (ESI) m/z 358.1 (M+Na)⁺.

(2-Phenylthiazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1e)

To a solution of 40e (0.357 g, 1 mmoL) in 40 mL anhydrous CH₂Cl₂ wasadded Dess-Martin reagent (0.848 g, 2 mmol). The mixture was allowed tostir for 30 min and quenched with sat. Na₂S₂O₃ solution, extracted withethyl acetate and dried with MgSO₄. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to give pure compound 1e (80.1%). ¹H NMR (CDCl₃) δ 8.33(s, 1H), 8.04 (m, 2H), 7.51 (m, 3H), 7.18 (s, 2H), 3.96 (s, 3H), 3.93(s, 6H); MS (ESI) m/z 378.1 (M+H)⁺.

Thiophene B Ring Synthesis of(5-Phenylthiophen-3-yl)(3,4,5-trimethoxyphenyl)methanone (1f) (FIG. 2)

N-Methoxy-N-methyl-5-phenylthiophene-3-carboxamide (38f)

To a mixture of 37f (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM(5.3 mmol) in CH₂Cl₂ (30 mL) was added HNCH₃OCH₃HCl salt (2.6 mmol) andstifling continued at RT for overnight. The reaction mixture was dilutedwith CH₂Cl₂ (20 mL) and sequentially washed with water, satd. NaHCO₃,brine and dried over MgSO₄. The solvent was removed under reducedpressure to yield a crude product, which was purified by columnchromatography to obtain pure compound 38f. (90.8%). ¹H NMR (CDCl₃) δ8.28 (d, 1H, J=1.5 Hz), 7.69 (d, 1H, J=1.5 Hz), 7.64 (d, 2H, J=7.0 Hz),7.44 (t, 2H, J=7.0 Hz), 7.35-7.32 (m, 1H), 6.78 (d, 1H, J=4.0 Hz), 3.86(s, 3H), 3.41 (s, 3H); MS (ESI) m/z 270.0 (M+Na)⁺.

(5-Phenylthiophen-3-yl)(3,4,5-trimethoxyphenyl)methanol (40f)

At −78° C., to a solution of 38f (2.5 mmol) in 5 mL THF under argonprotection was added a solution of LiAlH₄ in THF (1 N, 1.42 mL) andstirring continued at 1 h at −20° C. The reaction mixture was placed onan ice bath and quenched by 20% H₂SO₄ solution, extracted with ethylacetate and dried over MgSO₄. The solvent was removed under reducedpressure and purified by column chromatography to yield5-phenylthiophene-3-carbaldehyde (not shown) (84.8%). ¹H NMR (CDCl₃) δ9.98 (s, 1H), 8.04 (d, 1H, J=1.5 Hz), 7.86 (br, 1H), 7.61-7.58 (br, 2H),7.47-7.33 (m, 3H), 7.35-7.32 (m, 1H), 6.78 (d, 1H, J=4.0 Hz); MS (ESI)m/z 210.9 (M+Na)⁺. To a solution of 5-phenylthiophene-3-carbaldehyde(0.195 g, 1.04 mmoL) in 5 mL THF was added a THF solution of3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 2.3 mL, 1.14 mmol) at 0°C. The mixture was allowed to stir for 30 min and quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 40f. (70.5%).¹H NMR (CDCl₃) δ 7.55-7.52 (m, 2H), 7.40-7.35 (m, 3H), 7.30 (br, 1H),7.20 (br, 1H), 6.72 (s, 2H), 6.01 (d, 1H, J=3.9 Hz), 3.86 (s, 6H), 3.85(s, 3H), 2.42 (d, 1H, J=3.9 Hz); MS (ESI) m/z 339.1 (M-OH)⁻.

(5-Phenylthiophen-3-yl)(3,4,5-trimethoxyphenyl)methanone (1f)

To a solution of 40f (0.260 g, 0.73 mmoL) in 20 mL anhydrous CH₂Cl₂ wasadded Dess-Martin reagent (0.465 g, 1.36 mmol). The mixture was allowedto stir for 30 min and quenched with sat. Na₂S₂O₃ solution, extractedwith ethyl acetate and dried with MgSO₄. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to give pure compound 1f as light yellow crystals(60.9%). ¹H NMR (CDCl₃) δ 7.97 (d, 1H, J=1.5 Hz), 7.82 (d, 1H, J=1.5Hz), 7.59-7.57 (m, 2H), 7.45-7.34 (m, 3H), 7.19 (s, 2H), 3.95 (s, 3H),3.93 (s, 6H); MS (ESI) m/z 355.1 (M+H)⁺.

Piperidine B Ring Synthesis of(4-Phenylpiperidin-1-yl)(3,4,5-trimethoxyphenyl)methanone (1g) (FIG. 2)

(4-Phenylpiperidin-1-yl)(3,4,5-trimethoxyphenyl)methanone (1g)

To a mixture of 4-phenylpiperidine 41g (5 mmol), EDCI (6 mmol), HOBt(5.5 mmol) and NMM (6 mmol) in CH₂Cl₂ (50 mL) was added3,4,5-trimethoxybenzoic acid (5.3 mmol) and stirring continued at RT forovernight. The reaction mixture was diluted with CH₂Cl₂ (100 mL) andsequentially washed with water, satd. NaHCO₃, brine and dried overMgSO₄. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography to obtain purecompound 1g. (57.9%). ¹H NMR (CDCl₃) δ 7.35-7.21 (m, 5H), 6.66 (s, 2H),4.84 (br, 1H), 3.95 (br, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.20-2.87 (br,2H), 2.85-2.74 (tt, 1H, J=3.6 Hz, J=15.6 Hz) 1.92 (br, 2H), 1.70 (br,2H); MS (ESI) m/z 378.1 (M+Na)⁺.

Isoxazole B Ring Synthesis of(5-Phenylisoxazol-3-yl)(3,4,5-trimethoxyphenyl)methanone (1i) (FIG. 2)

(5-Phenylisoxazol-3-yl)(3,4,5-trimethoxyphenyl)methanol (40i)

To a solution of 5-phenylisoxazole-3-carbaldehyde 38i (0.365 g, 2.1mmol) in 15 mL THF was added a THF solution of3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 5.5 mL, 2.74 mmol) at 0°C. The mixture was allowed to stir for 30 min and quenched with satd.NH₄Cl, extracted with ethyl ether, dried with MgSO₄. The solvent wasremoved under reduced pressure to yield a crude product, which waspurified by column chromatography to obtain pure compound 40i as a whitesolid. (48.8%). ¹H NMR (CDCl₃) δ 7.78-7.77 (m, 2H), 7.48-7.46 (m, 3H),6.74 (s, 2H), 6.45 (s, 1H), 5.98 (d, 1H, J=3.5 Hz) 3.89 (s, 6H), 3.86(s, 3H), 2.77 (d, 1H, J=3.5 Hz); MS (ESI) m/z 364.1 (M+Na)⁺.

(5-Phenylisoxazol-3-yl)(3,4,5-trimethoxyphenyl)methanone (1i)

To a solution of 40i (0.110 g, 0.73 mmoL) in 8 mL anhydrous CH₂Cl₂ wasadded Dess-Martin reagent (0.274 g, 0.645 mmol). The mixture was allowedto stir for 30 min and quenched with sat. Na₂S₂O₃ solution, extractedwith ethyl acetate and dried with MgSO₄. The solvent was removed underreduced pressure to yield a crude product, which was purified by columnchromatography to give pure compound 1i (70.1%). ¹H NMR (CDCl₃) δ7.87-7.85 (m, 2H), 7.72 (s, 2H), 7.53-7.49 (m, 3H), 7.05 (s, 1H), 7.82(d, 1H, J=1.5 Hz), 3.97 (s, 3H), 3.96 (s, 6H); MS (ESI) m/z 362.1(M+H)⁺.

Pyrazole B Ring Synthesis of(3-Phenyl-1H-pyrazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1k) (FIG.2)

(3-Phenyl-1H-pyrazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1k)

was prepared using the same method as used of compound 1c from3-phenyl-1H-pyrazole-5-carboxylic acid. ¹H NMR (500 MHz, CDCl₃ δ 10.97(br, 1H), 7.77 (s, br, 2H), 7.48-7.38 (m, 5H), 7.14 (s, br, 1H), 3.96(s, 3H), 3.94 (s, 6H); MS (ESI) m/z 361.1 (M+Na)⁺, 337.0 (M−H)⁻.

Example 2 Synthesis of Compounds of this Invention Having Different YLinkers

The compounds of this invention possess different Y linkers. Suchcompounds, with different Y linkers, were synthesized according to FIGS.3 and 4.

Compound 1h was synthesized from2-phenyl-4,5-dihydro-thiazole-4-carboxylic acid 42a through three stepsdescribed before (Lu, Y.; Wang, Z.; Li, C. M.; Chen, J.; Dalton, J. T.;Li, W.; Miller, D. D., Synthesis, in vitro structure-activityrelationship, and in vivo studies of 2-arylthiazolidine-4-carboxylicacid amides as anticancer agents. Bioorg Med Chem 2010, 18, (2), 477-95which is incorporated herein by reference in its entirely). 1h wasconverted to oxime isomers 2e-cis,trans and 2f-cis,trans upon reactionwith hydroxylamines, NH₂OH or NH₂OCH₃. Assignments were made on thebasis of chemical and spectral data as described infra. An improvedBeckmann rearrangement readily produced the rearranged amides 2g and 2hfrom the two geometric stereoisomers 2e-cis and 2e-trans via theirreaction with tosyl chloride and subsequent basic aluminum oxide column.Hydrazide derivatives 2d-cis and 2d-trans were prepared by mixing 1hwith hydrazine hydrate in ethanol and refluxing for 24 h. Acrylonitriles2c-trans,cis were obtained from Wittig reaction of 1h with diethylcyanomethylphosphonate. Cyanoimine 2j was prepared using the procedureas by described by Cuccia (Cuccia, S. J.; Fleming, L. B.; France, D. J.,A novel and efficient synthesis of 4-phenyl-2-chloropyrimidines fromacetophenone cyanoimines. Synthetic Communications 2002, 32, (19),3011-3018., incorporated herein by reference in its entirely). Thecarbonyl group in compound 1h was also reduced to a secondary alcohol 2bor converted to an alkene (2a) as illustrated in FIG. 3.

Attempts to remove the carbonyl group between B and C rings in 1h,resulted in the formation of compound 2i as shown in FIG. 4. Introducingcis- and trans-double bonds into the carbonyl position formed compounds(3a and 3b), which were synthesized from a Wittig reaction with2-phenylthiazole-4-carbaldehyde. The sulfide compound 4a, sulfone 4b andsulfoxide 4c were prepared using 3-aminobiphenyl as starting materialthrough an initial Sandmeyer reaction to yield carbonodithioate 52a,followed by CuI catalyzed coupling reaction and m-CPBA oxidation.Sulfonamide linked compound 4d was prepared from reaction of3-biphenylsulfonyl chloride with 3,4,5-trimethoxyaniline in the presenceof NEt₃ in DMF.

Synthesis of (2-Phenyl-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone(1h) [FIG. 3]

(2-Phenyl-thiazol-4-yl)-(3,4,5-trimethoxy-phenyl)-methanone (1h)

A mixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol),EDCI (6 mmol) and HOBt (5 mmol) in CH₂Cl₂ (50 mL) was stirred for 10min. To this solution, NMM (5 mmol) and HNCH₃OCH₃ (5 mmol) were addedand stifling continued at RT for 6-8 h. The reaction mixture was dilutedwith CH₂Cl₂ (100 mL) and sequentially washed with water, satd. NaHCO₃,brine and dried over MgSO₄. The solvent was removed under reducedpressure to yield a crude product, which was purified by columnchromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acidmethoxymethylamide. A solution of2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1equiv) in CH₂Cl₂ was cooled to 0° C., and distilled DBU (2 equiv) wasadded. Bromotrichloromethane (1.7 equiv) was then introduced dropwisevia syringe over 10 min. The reaction mixtures were allowed to warm toRT and stirred overnight. Upon washing with satd. aqueous NH₄Cl (2×50mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combinedorganic layers were dried on MgSO₄, filtered and concentrated in vacuo.The residue was purified by flash chromatography as needed providing2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). ¹H NMR(300 MHz, CDCl₃) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H),3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)⁺. To a solution of3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF wascharged a solution of 2-phenyl-thiazole-4-carboxylic acidmethoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures werestirred for 30 min until amides disappeared on TLC plates. The reactionmixture was quenched with satd. NH₄Cl, extracted with ethyl ether, driedwith MgSO₄. The solvent was removed under reduced pressure to yield acrude product, which was purified by column chromatography to obtainpure compound 1h. Yield: 27.3%. ¹H NMR (300 MHz, CDCl₃) δ 8.29 (s, 1H),8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s,3H). MS (ESI) m/z 378.1 (M+Na)⁺.

Synthesis of4-(2-Methyl-1-(3,4,5-trimethoxyphenyl)prop-1-enyl)-2-phenylthiazole (2a)[FIG. 3]

4-(2-Methyl-1-(3,4,5-trimethoxyphenyl)prop-1-enyl)-2-phenylthiazole (2a)[FIG. 3]

At −78° C., to a solution of 223 mg isopropyl triphenylphosphoniumiodide (0.52 mmol) in 5 mL of THF was added dropwise 0.4 mL of 1.6 Nn-BuLi in hexane under Ar₂ protection. And the mixture was stirred at 0°C. for 40 min. A solution of 140 mg (0.39 mmol) of 1h in 5 mL of THF wasadded dropwise at 0° C., and the mixture was stirred for 1 h at RT. Thereaction mixture was treated with saturated NH₄Cl solution. After aconventional workup, column chromatography (silica gel, petroleumether/ethyl acetate) gave compound 2a (86 mg, 57.3%). ¹H NMR (300 MHz,CDCl₃) δ 7.98-7.97 (m, 2H), 7.45-7.40 (m, 3H), 6.77 (s, 1H), 6.48 (s,2H), 3.86 (s, 3H), 3.82 (s, 6H), 2.15 (s, 3H), 1.81 (s, 3H). MS (ESI)m/z 404.1 (M+Na)⁺.

Synthesis of (2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanol (2b)[FIG. 3]

2-Phenyl-4,5-dihydrothiazole-4-carboxylic acid (42a)

Benzonitrile (40 mmol) was combined with L-cysteine (45 mmol) in 100 mLof 1:1 MeOH/pH 6.4 phosphate buffer solution. The reaction was stirredat 40° C. for 3 days. The precipitate was removed by filtration, andMeOH was removed using rotary evaporation. To the remaining solution wasadded 1M HCl to adjust to pH=2 under 0° C. The resulting precipitate wasfiltered to yield a white solid2-phenyl-4,5-dihydrothiazole-4-carboxylic acid 42a, which was useddirectly to next step without purification.

2-Phenylthiazole-4-carbaldehyde (42b)

At −78° C., to a solution of 2-phenyl-thiazole-4-carboxylic acidmethoxymethylamide (1 equiv) in THF was added LiAlH₄ (1 equiv, 1 N inTHF) and stifling for 1 h at −20° C. The reaction mixture was placed onan ice bath and quenched by 20% H₂SO₄ solution, extracted with ethylacetate and dried over MgSO₄. The solvent was removed under reducedpressure and purified by column chromatography to yield 42b (45.8%). ¹HNMR (300 MHz, CDCl₃) δ 10.1 (s, 1H), 8.17 (s, 1H), 8.02-8.00 (m, 2H),7.50-7.48 (m, 3H). MS (ESI) m/z 244.1 (M+Na+MeOH)⁺.

(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanol (2b) [FIG. 3]

At 0° C., to a solution of 104 mg of 42b (0.55 mmol, 1 eq.) in 6 mL THFwas added 3,4,5-trimethoxyphenylmagnesium bromide (0.5 N in THF, 2.9mL). The mixtures were stirred for 30 min until aldehyde disappeared onTLC plates. The reaction mixture was quenched with satd. NH₄Cl,extracted with ethyl ether, dried with MgSO₄. The solvent was removedunder reduced pressure to yield a crude product, which was purified bycolumn chromatography to obtain pure compound (2b). ¹H NMR (300 MHz,CDCl₃) δ 7.95-7.92 (m, 2H), 7.44-7.43 (m, 4H), 6.97 (s, 1H), 6.76 (s,2H), 5.93 (d, 1H, J=3.6 Hz), 3.86 (s, 9H). MS (ESI) m/z 402.1 (M+Na)⁺.

Synthesis of(Z)-3-(2-phenylthiazol-4-yl)-3-(3,4,5-trimethoxyphenyl)acrylonitrile(2c-trans) and(E)-3-(2-phenylthiazol-4-yl)-3-(3,4,5-trimethoxyphenyl)acrylonitrile(2c-cis) [FIG. 3]

(Z)-3-(2-phenylthiazol-4-yl)-3-(3,4,5-trimethoxyphenyl)acrylonitrile(2c-trans)

To a solution of 0.4 mL of 2.5 N n-BuLi in hexane and 10 mL of THF wasadded dropwise a solution of 177 mg (1 mmol) of diethylcyanomethylphosphonate in 5 mL of THF at 0° C. under Ar₂. The ice bathwas removed, and the mixture was stirred at 25° C. for 40 min. Asolution of 200 mg (0.56 mmol) of 1h in 10 mL of THF was added dropwiseat 0° C., and the mixture was stirred for 1 h at RT. The reactionmixture was treated with saturated NH₄Cl solution. After a conventionalworkup, column chromatography (silica gel, petroleum ether/ethylacetate) gave compounds 2c-trans (83 mg) and 2c-cis (76 mg). ¹H NMR (300MHz, CDCl₃) δ 8.01-7.99 (m, 2H), 7.44-7.40 (m, 3H), 7.21 (s, 1H), 6.74(s, 2H), 6.67 (s, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 401.1(M+Na)⁺.

(E)-3-(2-phenylthiazol-4-yl)-3-(3,4,5-trimethoxyphenyl)acrylonitrile(2c-cis)

¹H NMR (300 MHz, CDCl₃) δ 8.07-8.05 (m, 2H), 7.49-7.46 (m, 4H), 6.66 (s,2H), 5.64 (s, 1H), 3.91 (s, 3H), 3.86 (s, 6H). MS (ESI) m/z 401.1(M+Na)⁺.

Synthesis of(Z)-4-(hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(2d-cis) and(E)-4-(hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(2d-trans) [FIG. 3]

(Z)-4-(hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(2d-cis)

To a mixture of 1h (230 mg, 0.65 mmol) in 3 mL CH₂Cl₂ and 3 mL ethanolwas added hydrazine hydrate (2 mL). Then the mixture was refluxed forovernight. After completion of the reaction, the residue was absorbed onsilica gel and purified by column chromatography to give compounds2d-cis (80 mg) and 2d-trans (56 mg). ¹H NMR (300 MHz, CDCl₃) δ 8.01-7.98(m, 2H), 7.49-7.46 (m, 5H), 7.33 (s, 1H), 6.82 (s, 2H), 3.87 (s, 3H),3.85 (s, 6H). MS (ESI) m/z 370.1 (M+H)⁺.

(E)-4-(hydrazono(3,4,5-trimethoxyphenyl)methyl)-2-phenylthiazole(2d-trans)

¹H NMR (300 MHz, CDCl₃) δ 8.04-8.01 (m, 2H), 7.44-7.40 (m, 3H), 6.95 (s,1H), 6.65 (s, 2H), 5.62 (s, 2H), 3.93 (s, 3H), 3.87 (s, 6H). MS (ESI)m/z 370.1 (M+H)⁺.

Synthesis of (Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanoneoxime (2e-cis) and(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime(2e-trans) [FIG. 3]

(Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime(2e-cis)

To a suspension of 1h (210 mg, 0.59 mmol) in 10 mL ethanol was added anaqueous solution (2 mL) of hydroxylamine hydrochloride (127 mg, 1.83mmol). Then 2 mL 1 N NaOH was added dropwise to the reaction mixture andthe mixture was stirred at 55° C. for 3 h. After completion of thereaction, the residue was absorbed on silica gel and purified by columnchromatography to give compounds 2e-cis (85 mg) and 2e-trans (50 mg). ¹HNMR (300 MHz, DMSO-d₆) δ 11.95 (s, 1H), 8.35 (s, 1H), 7.91-7.89 (m, 2H),7.50-7.44 (br, 3H), 6.85 (s, 2H), 3.73 (s, 6H), 3.70 (s, 3H). MS (ESI)m/z 393.1 (M+Na)⁺; 368.9 (M−H)⁻.

(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone oxime2e-trans)

¹H NMR (300 MHz, DMSO-d₆) δ 11.49 (s, 1H), 7.92-7.89 (m, 2H), 7.64 (s,1H), 7.51-7.49 (m, 3H), 7.34 (s, 1H), 6.75 (s, 2H), 3.75 (s, 6H), 3.72(s, 3H). MS (ESI) m/z 393.1 (M+Na)⁺; 368.9 (M−H)⁻.

Synthesis of (Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanoneO-methyl oxime (2f-cis) and(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone O-methyloxime (2f-trans) [FIG. 3]

(Z)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone O-methyloxime (2f-cis)

To a suspension of 1h (110 mg, 0.59 mmol) in 10 mL pyridine was addedO-methylhydroxylamine hydrochloride (52 mg, 0.63 mmol) and the mixturewas stirred at 60° C. for overnight. The reaction was quenched with 1 NHCl solution, extracted with ethyl acetate and dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was purified by column chromatography to give pure compounds2f-cis (41 mg) and 2f-trans (33 mg). ¹H NMR (500 MHz, CDCl₃) δ 8.13 (s,1H), 7.96-7.94 (m, 2H), 7.45-7.44 (m, 3H), 6.94 (s, 2H), 4.13 (s, 3H),3.91 (s, 6H), 3.88 (s, 3H). MS (ESI) m/z 407.2 (M+Na)⁺.

(E)-(2-Phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone O-methyloxime (2f-trans)

¹H NMR (500 MHz, CDCl₃) δ 8.00-7.98 (m, 2H), 7.44-7.43 (m, 3H), 7.28 (s,1H), 6.70 (s, 2H), 4.08 (s, 3H), 3.91 (s, 6H), 3.85 (s, 3H). MS (ESI)m/z 407.0 (M+Na)⁺.

Synthesis of 2-Phenyl-N-(3,4,5-trimethoxyphenyl)thiazole-4-carboxamide(2g) [FIG. 3]

2-Phenyl-N-(3,4,5-trimethoxyphenyl)thiazole-4-carboxamide (2g)

To a solution of 2e-cis (21 mg, 0.06 mmol) in 5 mL CH₂Cl₂ was addedp-toluenesulfonyl chloride (23 mg, 0.12 mmol) and NaH (5 mg, 60% inlight mineral oil). Then the reaction mixture was stirred for 20 min.After completion of the reaction, the residue was absorbed on silica geland purified by Al₂O₃ column chromatography to give compound 2g (15 mg).¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 1H), 8.19 (s, 1H), 8.02-7.99 (m, 2H),7.52-7.50 (m, 3H), 7.07 (s, 2H), 3.92 (s, 6H), 3.85 (s, 3H). MS (ESI)m/z 371.1 (M+H)⁺.

Synthesis of 3,4,5-Trimethoxy-N-(2-phenylthiazol-4-yl)benzamide (2h)[FIG. 3]

3,4,5-Trimethoxy-N-(2-phenylthiazol-4-yl)benzamide (2h)

To a solution of 2e-trans (26 mg, 0.07 mmol) in 5 mL CH₂Cl₂ was addedp-toluenesulfonyl chloride (27 mg, 0.14 mmol) and NaH (5 mg, 60% inlight mineral oil). Then the reaction mixture was stirred for 20 min.After completion of the reaction, the residue was absorbed on silica geland purified by Al₂O₃ column chromatography to give compound 2h (15 mg).¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 7.94-7.91 (m, 2H), 7.83 (s, 1H),7.48-7.46 (m, 3H), 7.18 (s, 2H), 3.97 (s, 6H), 3.94 (s, 3H). MS (ESI)m/z 393.1 (M+Na)⁺.

Synthesis ofN-((2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)cyanamide(2j) [FIG. 3]

N-((2-phenylthiazol-4-yl)(3,4,5-trimethoxyphenyl)methylene)cyanamide(2j)

100 mg of 1h (0.28 mmol, 1 eq.) was dissolved in 10 mL methylenechloride. Titanium tetrachloride in methylene chloride (1.0 N, 0.7 mL,2.5 eq.) was added dropwise at 0° C. and stirred for 30 min.Bis-trimethylsilylcarbodiimide (2.4 eq.) in 2 mL methylene chloride wasadded and the reaction stirred overnight protected from air andmoisture. The reaction was treated with ice-water mixture followed byextraction with methylene chloride. The organic phase was dried overmagnesium sulfate, filtered through celite and concentrated to give thecrude acetophenone cyanoimines which were purified by flash column asisomers with a ratio of 3:7. ¹H NMR (300 MHz, CDCl₃) δ 8.72 (br, 0.3 H),8.63 (s, 0.7 H), 8.09-8.07 (m, 1.4 H), 7.99 (br, 0.6H), 7.58-7.56 (br,3H), 7.26 (s, 1.4 H), 7.18 (s, 0.6 H), 3.84, 3.83 (s, s, 6H), 3.82 (s,3H). MS (ESI) m/z 402.1 (M+Na)⁺.

Synthesis ofN-((4-hydroxy-3,5-dimethoxyphenyl)(2-phenylthiazol-4-yl)methylene)cyanamide(32)

N-((4-hydroxy-3,5-dimethoxyphenyl)(2-phenylthiazol-4-yl)methylene)cyanamide(32)

was obtained as a by-product from synthesis of 2j. ¹H NMR (500 MHz,CDCl₃) δ 8.23 (s, 1H), 8.02 (m, 2H), 7.92 (s, 2H), 7.55 (m, 3H), 6.02(s, 1H), 3.99 (s, 6H). MS (ESI) m/z 364.1 (M+H)⁺.

Synthesis of (Z)-2-Phenyl-4-(3,4,5-trimethoxystyryl)thiazole (3a) and(E)-2-Phenyl-4-(3,4,5-trimethoxystyryl)thiazole (3b) [FIG. 4]

(Z)-2-Phenyl-4-(3,4,5-trimethoxystyryl)thiazole (3a)

Triphenylphosphine (3.41 g, 13 mmol) was added to a solution of5-(bromomethyl)-1,2,3-trimethoxybenzene (2.61 g, 10 mmol) in dry THF (30mL). The mixture was refluxed with stirring for 6 h. The resulting whitesolid was filtered and washed with ether/hexane to afford the product3,4,5-trimethoxybenzyltriphenylphosphonium bromide in 96.4% yield. ¹HNMR (500 MHz, CDCl₃) δ 7.77-7.73, 7.65-7.61 (m, 15H), 6.44 (d, 2H, J=1.5Hz), 5.37 (d, 2H, J=14 Hz), 3.76 (s, 3H), 3.51 (d, 6H); MS (ESI) m/z443.1 (M-Br]⁺. At −78° C., n-BuLi (0.42 mL, 2.5 N in hexane) was addedto a solution of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (500mg, 0.96 mmol) in 10 mL THF. After stifling at RT for 2 h, aldehyde 42b(109 mg, 0.58 mmol) in 3 mL THF was charged and stirred for 30 min. Thereaction mixture was treated with saturated NH₄Cl solution. After aconventional workup, column chromatography (silica gel, petroleumether/ethyl acetate) gave compounds 3a (57 mg) and 3b (99 mg). ¹H NMR(500 MHz, CDCl₃) δ 7.90-7.89 (m, 2H), 7.42-7.40 (m, 3H), 7.07 (s, 1H),6.71 (s, 2H), 6.66 (s, 1H), 3.87 (s, 6H), 3.75 (s, 3H); MS (ESI) m/z376.1 (M+Na)⁺.

(E)-2-Phenyl-4-(3,4,5-trimethoxystyryl)thiazole (3b)

¹H NMR (500 MHz, CDCl₃) δ 8.03-8.01 (m, 2H), 7.52 (d, 1H, J=16 Hz),7.47-7.44 (m, 3H), 7.16 (s, 1H), 7.05 (d, 1H, J=16 Hz), 6.79 (s, 2H),3.92 (s, 6H), 3.88 (s, 3H). MS (ESI) m/z 354.1 (M+H)⁺.

Synthesis of Biphenyl-3-yl(3,4,5-trimethoxyphenyl)sulfane (4a),3-(3,4,5-Trimethoxyphenylsulfonyl)biphenyl (4b) and3-(3,4,5-Trimethoxyphenylsulfinyl)biphenyl (4c) [FIG. 4]

S-Biphenyl-3-yl O-ethyl carbonodithioate (52a)

To a solution of 1 equiv. of biphenyl-3-amine (1 g, 5.92 mmol) in water(7.3 mL) at 0° C. was added concentrated hydrochloric acid (1 mL). Acold solution of 1.1 equiv. of sodium nitrite (450 mg, 6.5 mmol) inwater (3 mL) was added slowly and stirred for 15 min. The cold diazoniumsolution was added slowly to a solution of 1.3 equiv. of potassium ethylxanthate (1.16 g, 1.3 mmol) in water (1.3 mL) at 45° C. The reactionmixture was stirred for an additional 30 min at 45° C. and then cooledto RT. The reaction mixture was extracted with diethyl ether (3×50 mL).The combined organic extracts were washed with 1N NaOH solution (100mL), water (3×50 mL), brine (50 mL), dried over MgSO4, filtered andevaporated under reduced pressure. The resulting crude xanthate 52a wasused directly in the next step without further purification. MS (ESI)m/z 275.0 (M+H)⁺.

Biphenyl-3-yl(3,4,5-trimethoxyphenyl)sulfane (4a)

To a solution of 52a (1.1 g, crude compound) in ethanol (8 mL) was addedpotassium hydroxide (2.1 g, 12 mL) and heated to reflux for overnight.The solution was cooled to RT and the ethanol was evaporated underreduced pressure. The residue was dissolved in water and washed withdiethyl ether (10 mL). The aqueous layer was acidified with 2 N HCl andextracted with diethyl ether (3×50 mL). The organic extracts were washedwith water (50 mL), brine (50 mL), dried over MgSO₄, filtered andevaporated under reduced pressure to afford 0.85 g (77.3%) of crudebiphenyl-3-thiol product (overall, 3 steps). Into a round-bottomedflask, stirred magnetically, were placed 0.1 g (1.04 mmol) of sodiumtert-butoxide and 83 mg of copper iodide (0.43 mmol). After the reactionvessel was sealed, 0.13 g (0.71 mmol) of 4-methoxybenzenethiol and 0.19g (0.65 mmol) of 5-iodo-1,2,3-trimethoxybenzene in 3.0 mL of toluenewere injected through the septum. The reaction mixture was heated forovernight at 110° C. Purification was performed by flash chromatography,and an amorphous solid was obtained (40% yield). ¹H NMR (500 MHz, CDCl₃)δ 7.54-7.52 (m, 3H), 7.44-7.41 (m, 3H), 7.37-7.33 (m, 2H), 7.23 (s, br,1H), 6.69 (s, 2H), 3.86 (s, 3H), 3.80 (s, 6H). MS (ESI) m/z 353.2(M+H)⁺.

3-(3,4,5-Trimethoxyphenylsulfonyl)biphenyl (4b)

To a solution of 60 mg (0.17 mmol) of compound 4a and 5 mL ofdichloromethane was added very slowly 2 equiv. of m-CPBA over 3 h.Sulfoxide formation was monitored by thin-layer chromatography.Purification was performed with a flash chromatographic column, and anamorphous powder of (4b) was obtained (73% yield). ¹H NMR (500 MHz,CDCl₃) δ 8.14 (br, 1H), 7.89 (d, 1H), 7.78 (d, 1H), 7.59-7.56 (m, 3H),7.49-7.39 (m, 3H), 7.19 (s, 2H), 3.89 (s, 6H), 3.87 (s, 3H). MS (ESI)m/z 385.0 (M+Na)⁺.

3-(3,4,5-Trimethoxyphenylsulfinyl)biphenyl (4c)

At 0° C., to a solution of 500 mg (1.42 mmol) of compound (4a) and 5 mLof dichloromethane was added very slowly 1 equiv. of m-CPBA over 3 h.Sulfoxide formation was monitored by thin-layer chromatography.Purification was performed with a flash chromatographic column, and anamorphous powder of (4c) was obtained (87% yield). ¹H NMR (500 MHz,CDCl₃) δ 7.92 (br, 1H), 7.71 (d, 2H), 7.62-7.60 (m, 3H), 7.58-7.40 (m,4H), 6.94 (s, 2H), 3.79 (s, 3H), 3.74 (s, 6H). MS (ESI) m/z 369.1(M+H)⁺.

Synthesis of N-(3,4,5-trimethoxyphenyl)biphenyl-3-sulfonamide (4d) [FIG.4]

N-(3,4,5-Trimethoxyphenyl)biphenyl-3-sulfonamide (4d)

A mixture of 65 mg of biphenyl-3-sulfonyl chloride (0.25 mmol), 44 mg of3,4,5-trimethoxyaniline (0.24 mmol), and 0.3 mmol of triethylamine in 5mL DMF was stirred overnight. The reaction mixture was treated withwater and extracted with ethyl acetate. After a conventional workup,column chromatography (silica gel, petroleum ether/ethyl acetate) gave88 mg compounds (4d) (91.7%). ¹H NMR (500 MHz, CDCl₃) δ 7.96 (t, 1H,J=1.8 Hz), 7.81-7.74 (m, 2H), 7.57-7.40 (m, 6H), 6.33 (s, 2H), 3.86 (s,3H), 3.80 (s, 6H). MS (ESI) m/z 422.1 (M+Na)⁺.

2-Phenyl-4-(3,4,5-trimethoxyphenyl)thiazole (2i) [FIG. 4]

2-Phenyl-4-(3,4,5-trimethoxyphenyl)thiazole (2i)

Bromine (160 mg, 1 mmol) was added dropwise to a stirred solution of an1-(3,4,5-trimethoxyphenyl)ethanone (210 mg, 1 mmol) in ethanol (30 mL)and the solution was stirred at 0° C. for 1 h and then poured into waterto form a precipitate. This was recrystallized from ethanol to givebromoacetophenone (70%) and used directly for next step. A mixture ofbromoacetophenone (288 mg, 1 mmol) and benzothioamide (137 mg, 1 mmol)in ethanol was refluxed for 1 h. The reaction mixture was concentratedin vacuo and purified with flash column to give 2i (167 mg, 51.1%). ¹HNMR (500 MHz, CDCl₃) δ 8.05-8.03 (m, 2H), 7.48-7.44 (m, 3H), 7.41 (s,1H), 7.22 (s, 2H), 3.97 (s, 6H), 3.89 (s, 3H). MS (ESI) m/z 350.1(M+Na)⁺.

Example 3 Synthesis of Methoxy Benzoyl Thiazole Compounds HavingDifferent “A” Rings and/or Substituted “A” Ring

The compounds of this invention possess different substituted orunsubstituted A rings such as phenyl or indolyl. Such compounds weresynthesized according to FIGS. 5 and 6.

Hydroxyl and aminomethyl were introduced at the para-position of thephenyl A-ring, as well as the phenyl was replaced with 5-indolyl and2-indolyl rings. Weinreb amides 57a, 61a, 65a, and 67a were prepared bythe procedure presented in FIG. 5 using aryl nitriles as startingmaterials. 2-Cyano-indole 60a was prepared according to a standardprocedure (Pletnev, A. A.; Tian, Q.; Larock, R. C., Carbopalladation ofnitriles: synthesis of 2,3-diarylindenones and polycyclic aromaticketones by the Pd-catalyzed annulation of alkynes and bicyclic alkenesby 2-iodoarenenitriles. J Org Chem 2002, 67(26), 9276-87; incorporatedherein by reference in its entirely). Protections of hydroxyl (TBDMSC1),indolyl (PhSO₂Cl) and amino (Boc₂O) groups were used in preparations.Deprotection of TBDMS and oxidation from thiazoline (58a) to thiazole(2l) took place in one-step using TBAF/THF solution. Thisthiazoline-thiazole oxidation takes place spontaneously in the reactionof thiazoline Weinreb amide and Grignard reagent. The same phenomena isobserved during preparation of the indole compounds 62a and 66a.

Compound 62a was separated as a pure thiazole compound after reactionwith 3,4,5-trimethoxphenyllithium without the need for furtheroxidation. Compound 66a was obtained by removing the phenylsulfonylprotecting groups in hot NaOH ethanol solution. para-OH and NH₂ on the Aring of 2l and 2r were obtained by similar Grignard reactions from theWeinreb amides 58a and 68a. Compound 2r was further converted to the HClsalt (2r-HCl) and the HCl salt of monomethyl amine 2s-HCl using NaH/MeIconditions and dimethylamine 2u under HCHO/NaBH₃CN conditions.

Substituted A Ring Synthesis of(2-(4-Hydroxyphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (2l)[FIG. 5]

(R)-2-(4-Hydroxyphenyl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(57a) was synthesized using the same method as used for 38d

Quantitative yield. ¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, 2H, J=8.5 Hz),6.84 (br, 1H), 6.73 (d, 2H, J=8.5 Hz), 5.64 (t, br, 1H), 3.87 (s, 3H),3.30 (s, 3H). MS (ESI) m/z 289.0 (M+Na)⁺, 264.9 (M−H)⁻.

(R)-(2-(4-(tert-Butyldimethylsilyloxy)phenyl)-4,5-dihydrothiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(58a) was synthesized using the same method as used for (35a)-seeExample 1

67.0% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, 2H, J=8.7 Hz), 7.61 (s,2H), 6.83 (d, 2H, J=8.7 Hz), 5.95 (dd, 1H, J=8.1 Hz, 9.0 Hz), 4.09, (dd,1H, J=7.8 Hz, 11.1 Hz), 3.95 (s, 3H), 3.94 (s, 6H), 3.55 (dd, 1H, J=9.3Hz, 11.1 Hz), 0.97 (s, 9H), 0.19 (s, 6H). MS (ESI) m/z 510.4 (M+Na)⁺,486.0 (M−H)⁻.

(2-(4-Hydroxyphenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (2l)

At 0° C., to a solution of 58a (0.2 mmol) in 5 mL CH₂Cl₂ was added asolution of tetrabutylammonium fluoride in THF (1 N, 0.6 mmol) andstirred at RT for around 14 h until reaction was finished by TLCmonitor. 67.0% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 10.1 (s, 1H), 8.51 (s,1H), 7.85 (d, 2H, J=8.50 Hz), 7.62 (s, 2H), 6.91 (d, 2H, J=8.5 Hz), 3.86(s, 6H), 3.79 (s, 3H). MS (ESI) m/z 394.1 (M+Na)⁺, 369.9 (M−H)⁻.

(2-(4-(Aminomethyl)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2r or 2r-HCl) [FIG. 5]

(R)-tert-Butyl4-(4-(methoxy(methyl)carbamoyl)-4,5-dihydrothiazol-2-yl)benzyl carbamate(67a)

4-(Aminomethyl)benzonitrile (25.09 g, 0.149 mol) and L-cysteine (18.1 g,0.149 mol) were suspended in 500 mL MeOH and pH 6.4 buffer solutions(1:1) and stirred for 3 days at RT. Triethylamine (30 mL) was added tothe mixture and Boc₂O (68 g, 0.3 μmol) was added to this mixture andstirred for 2 h. The solvents were removed and filtered to yield whitesolid(R)-2-(4-((tert-butoxycarbonylamino)methyl)phenyl)-4,5-dihydrothiazole-4-carboxylicacid (38.4 g, 76.8%). Compound 67a was obtained from this acid followingthe same method as used for 38d. Yield: 84.4%. ¹H NMR (500 MHz, CDCl₃) δ7.75-7.77 (d, 2H, J=7.5 Hz), 7.27-7.26 (d, 2H, J=7.5 Hz), 7.23 (s, 1H),5.62 (br, 1H), 4.87 (br, 1H), 4.30 (br, 2H), 3.86 (s, 3H), 3.78 (t,J=10.0 Hz, 1H), 3.48-3.4 (m, 1H), 3.25 (s, 3H), 1.42 (s, 9H). MS (ESI)m/z 402.1 (M+Na)⁺, 378.0 (M−H)⁻.

tert-Butyl 4-(4-(3,4,5-trimethoxybenzoyl)thiazol-2-yl)benzylcarbamate(68a)

A mixture of 67a (2.5 mmol), CBrCl₃ (3.2 mmol) and DBU (5.0 mmol) inCH₂Cl₂ (20 mL) was stirred overnight. The reaction mixture was absorbedon silica gel and purified by column chromatography to yield anintermediate thiazole Weinreb amide. To a solution of(3,4,5-trimethoxyphenyl)magnesium bromide (0.5 M, 5.5 mL) in THF wasadded a solution of the intermediate thiazole Weinreb amide (1.83 mmol)in 10 mL THF under 0° C. and stirred for 30 min. The reaction mixturewas quenched with satd. NH₄Cl, extracted with ethyl ether, dried withMgSO₄. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography to obtain purecompound as a light yellow solid (32.3%). ¹H NMR (300M, CDCl₃) δ 8.27(s, 1H), 7.98 (d, 2H, J=8.1 Hz), 7.78 (s, 2H), 7.39 (d, 2H, J=8.1 Hz),7.27-7.26 (d, 2H, J=7.5 Hz), 7.23 (s, 1H), 4.93 (br, 1H), 4.37 (br, d,1H), 3.96 (s, 3H), 3.95 (s, 6H), 1.47 (s, 9H); MS (ESI) m/z 507.1(M+Na)⁺.

(2-(4-(Aminomethyl)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2r or 2r-HCl)

At 0° C., to a solution of 68a (200 mg) in 10 mL CH₂Cl₂ was added asolution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT for 4 h.The precipitate (2r) was filtered and washed with diethyl ether. Yield:81.3%. ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.38 (br, 3H), 8.10 (d,2H, J=8.4 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.62 (s, 2H), 4.11 (s, 2H), 3.87(s, 6H), 3.80 (s, 3H). MS (ESI) m/z 385.1 (M+H)⁺.

(2-(4-((Dimethylamino)methyl)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2u or 2u-HCl) [FIG. 5]

tert-Butylmethyl(4-(4-(3,4,5-trimethoxybenzoyl)thiazol-2-yl)benzyl)carbamate (71a)

At 0° C., to a solution of compound 68a (100 mg, 0.2 mmol) in 5 mL DMFwas added sodium hydride (10 mg, 0.2 mmol), then iodomethane (77 mg, 0.4mmol) was added to the reaction mixture and stirred at RT overnight. Themixture was quenched with a sat. NaHCO₃ solution, extracted with ethylacetate and dried with MgSO₄. The solvent was removed under reducedpressure to yield a crude product, which was purified by columnchromatography to obtain pure compound 71a. Yield: 61.3%. ¹H NMR (500MHz, DMSO-d₆) δ 8.30 (s, 1H), 8.02 (d, 2H, J=8.0 Hz), 7.82 (s, 2H), 7.36(br, 2H), 4.50 (s, 2H), 4.00 (s, 3H), 3.98 (s, 6H), 2.90 (d, br, 3H),1.50 (s, 9H). MS (ESI) m/z 521.2 (M+Na)⁺, 496.9 (M−H)⁻.

(2-(4-((Methylamino)methyl)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2s or 2s-HCl)

At 0° C., to a solution of 71a (60 mg) in 5 mL CH₂Cl₂ was added asolution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT forovernight. The precipitate (2s-HCl) was filtered and washed with diethylether. Yield: 81.3%. ¹H NMR (500 MHz, CDCl₃) δ 10.0 (s, 1H), 8.29 (s,1H), 8.05 (d, 2H, J=6.0 Hz), 7.74 (s, 2H), 7.72 (d, 2H, J=6.0 Hz), 4.15(s, 2H), 3.99 (s, 3H), 3.96 (s, 6H), 2.61 (s, 3H). MS (ESI) m/z 399.1(M+H)⁺.

(2-(4-((Dimethylamino)methyl)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride (2u or 2u-HCl)

To a solution of 2r (53 mg, 0.14 mmol) in 5 mL CH₂Cl₂ was addedformaldehyde solution (37% in H₂O, 340 mg, 4.2 mmol), and sodiumcyanoborohydride (34 mg, 0.55 mmol), the reaction mixture was absorbedon silica gel and free base was purified after flash column (41 mg,70.9%). At 0° C., to a solution of free base (41 mg) in 5 mL CH₂Cl₂ wasadded a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT forovernight. The precipitate (2u) was filtered and washed with diethylether. Yield: 71.3%. ¹H NMR (500 MHz, CDCl₃) δ 13.0 (s, 1H), 8.34 (s,1H), 8.13 (d, 2H, J=7.0 Hz), 7.82 (d, 2H, J=7.5 Hz), 7.75 (s, 2H), 4.24(s, 2H), 3.99 (s, 3H), 3.97 (s, 6H), 2.83 (s, 6H). MS (ESI) m/z 413.1(M+H)⁺.

2-(4-(4-(3,4,5-Trimethoxybenzoyl)thiazol-2-yl)phenyl)acetonitrile (2n)

2-(4-(4-(3,4,5-Trimethoxybenzoyl)thiazol-2-yl)phenyl)acetonitrile (2n)

was prepared using the same method as used of compound 1h fromterephthalonitrile and cysteine. 1H NMR (500 MHz, CDCl₃) δ 8.30 (s, 1H),8.04 (d, 2H), 7.76 (s, 2H), 7.46 (d, 2H), 3.97 (s, 3H), 3.95 (s, 6H),3.83 (s, 2H).

Synthesis of(2-(4-(Dimethylamino)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(2o)

(2-(4-(Dimethylamino)phenyl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(2o)

was prepared using the same method as used of compound 1h from4-(dimethylamino)benzonitrile and cysteine. ¹H NMR (300 MHz, CDCl₃) δ8.12 (s, 1H), 7.88 (d, 2H), 7.80 (s, 2H), 6.73 (d, 2H), 3.96 (s, 3H),3.95 (s, 6H), 3.05 (s, 6H); MS (ESI) m/z 421.1 (M+Na)⁺.

Indolyl A Ring Synthesis of(2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (62a)[FIG. 5]

1H-Indole-2-carbonitrile (60a)

To a cooled solution of indole-2-carboxylic acid (2.0 g, 12.4 mmol) in60 mL of anhydrous Et₂O was added 1.9 mL of SOCl₂ (26 mmol). Afterstirring for 40 min at RT, the ether was removed under reduced pressureat a temperature not exceeding 35° C. The obtained acyl chloride wasdissolved in 40 mL of anhydrous Et₂O and the resulting solution wasadded immediately to a stirred solution of liquid ammonia in 80 ml ofEt₂O. The reaction mixture was stirred at RT for 24 h. The solvent wasthen evaporated under reduced pressure, and the whiteindole-2-carboxamide was crystallized from 50% aq EtOH and dried in air,after which it was dissolved in POCl₃ and heated under reflux for 5 min.The cooled solution was poured onto crushed ice and aq NH₄OH was addedto maintain a basic pH. The aqueous mixture was extracted with Et₂O, theextracts were dried over Na₂SO₄ and evaporated. The brownindole-2-carbonitrile 60a (63.3% overall yield from indole-2-carboxylicacid) was obtained. ¹H NMR (500 MHz, CDCl₃) δ 8.56 (br, s, 1H), 7.68 (d,1H, J=8.0 Hz), 7.43-7.34 (m, 2H), 7.24-7.21 (m, 2H). MS (ESI) m/z 144.0(M+H)⁺, 140.8 (M−H)⁻.

(R)-2-(1H-indol-2-yl)-N-methoxy-N-methyl-4,5-dihydrothiazole-4-carboxamide(61a) was synthesized using the same method as used of 38d

67.1% yield. ¹H NMR (300 MHz, CDCl₃) δ 9.06 (s, br, 1H), 7.64 (d, 2H,J=8.1 Hz), 7.36-7.24 (m, 2H), 7.12 (dt, 1H, J=8.1 Hz, 1.2 Hz), 6.95 (d,1H, J=1.8 Hz), 5.60 (t, br, 1H, J=8.7 Hz), 3.86 (s, 3H), 3.78 (t, 1H,J=10.2 Hz), 3.58 (dd, 1H, J=9.0 Hz, 10.2 Hz), 3.30 (s, 3H). MS (ESI) m/z312.1 (M+Na)⁺, 287.9 (M−H)⁻.

(2-(1H-indol-2-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (62a)was synthesized from 61a using the same method as used for 35a

45.8% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.11 (s, 1H),7.66 (d, 1H, J=8.0 Hz), 7.46 (s, 2H), 7.42 (d, 1H, J=8.0 Hz), 7.29 (t,1H, J=7.5 Hz), 7.16 (t, 1H, J=7.5 Hz), 7.10 (s, 1H), 3.97 (s, 3H), 3.93(s, 6H). MS (ESI) m/z 417.1 (M+Na)⁺, 392.9 (M−H)⁻.

Synthesis of(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (66a)[FIG. 5]

(R)-2-(1-(Phenylsulfonyl)-1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxylicacid (64a)

(R)-2-(1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxylic acid 63a wassynthesized using the same method as used for 42a from1H-indole-5-carbonitrile and used without further purification. To avigorously stirring solution of 63a (1 mmol) and tetrabutylammoniumhydrogen sulfate (0.15 mmol) in toluene (10 mL) at 0° C. was added 50%aqueous sodium hydroxide (10 mL) and sulfonyl chloride (2 mmol). Theresultant solution was stirred at RT for 6 h. Then 1N HCl was added toacidify the mixture to pH=2 and extracted with CH₂Cl₂, the organic layerwas separated and dried (MgSO₄); then evaporated to dryness to yield64a, which were used in subsequent steps without further purification.

(R)—N-methoxy-N-methyl-2-(1-(phenylsulfonyl)-1H-indol-5-yl)-4,5-dihydrothiazole-4-carboxamide(65a) was prepared from 64a with the same method as used for 38d

57.1% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (m, 2H), 7.77 (m, 3H), 7.51(d, 1H, J=3.0 Hz), 7.46 (t, 1H), 7.35 (t, 1H), 6.61 (d, 1H), 5.58 (br,t, 1H) 3.82 (s, 3H), 3.73 (t, 1H), 3.43 (m, 1H), 3.21 (s, 3H). MS (ESI)m/z 452.1 (M+Na)⁺.

(2-(1H-indol-5-yl)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (66a)

To a solution of n-BuLi (1.6 M, 1.7 mL) in 8 mL THF was added a solutionof 3,4,5-trimethoxybromobenzene (2.47 mmol) in 3 mL THF under −78° C.The mixture was allowed to stir for 2 h and a solution of Weinreb amide65a (1.24 mmol) in 3 mL THF was charged. The temperature was allowed toincrease at RT and stirred overnight. The reaction mixture was quenchedwith satd. NH₄Cl, extracted with ethyl ether, dried with MgSO₄. Thesolvent was removed under reduced pressure to yield a crude product,which was refluxed in 1N NaOH in 5 mL ethanol solution to obtain thedeprotected compound 66a and purified by column chromatography to obtainpure compound as a light yellow solid (36.3%). ¹H NMR (300M, CDCl₃) δ8.36 (br, s, 1H), 8.31 (s, 1H), 8.21 (s, 1H), 7.92, 7.89 (dd, 1H, J=1.8,2.7 Hz), 7.46 (d, 1H) 7.62 (s, 2H, J=8.7 Hz), 7.29 (t, 1H, J=2.7 Hz),6.64 (br, 1H), 3.97 (s, 6H), 3.97 (s, 3H); MS (ESI) m/z 417.1 (M+Na)⁺,392.9 (M−H)⁻.

Synthesis of (2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8)

(2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8)

was prepared using the similar method as used of compound 1h from2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. ¹HNMR (500 MHz, CDCl₃) δ 9.39 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.06(s, 1H), 8.03 (dd, 1H), 7.66 (d, 1H), 7.51 (d, 1H), 7.41 (d, 1H), 7.33(t, 1H), 7.29 (d, 1H), 7.15 (t, 1H), 7.09 (d, 1H), 6.72 (s, 1H). MS(ESI) m/z 366.1 (M+Na)⁺, 341.9 (M−H)⁻.

Synthesis of (2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone(21)

(2-(1H-indol-2-yl)thiazol-4-yl)(1H-indol-5-yl)methanone (21)

was prepared using the similar method as used of compound 1h from2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. ¹HNMR (500 MHz, CDCl₃) δ 9.60 (s, 1H), 9.26 (s, 1H), 8.31 (s, 1H), 8.03(s, 1H), 7.83 (dd, 1H), 7.69 (d, 1H), 7.53-7.49 (m, 2H), 7.41 (t, 1H),7.33 (t, 1H), 7.21-7.18 (m, 2H), 7.13 (s, 1H). MS (ESI) m/z 366.1(M+Na)⁺, 341.9 (M−H)⁻.

Example 4 Synthesis of Compounds of this Invention Having a NitrogenLinker (X═NH)

To improve bioavailability, an NH linker was introduced between A phenyland B thiazole rings. This new series of compounds was synthesized asshown in FIG. 6. Reaction of 3-bromo-2-oxopropanoic acid ethyl ester andarylthiourea in ethanol under 65° C. produced2-(arylamino)-thiazole-4-carboxylic acids 73a-d with high yields. Theseacids were converted to Weinreb amides 74a-d, followed by reactions with3,4,5-trimethoxphenyllithium that yielded aniline linked free bases5a-d, which can be converted into HCl salts 5Ha-d.

Synthesis of(2-(Phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonederivatives (5a-d) and their HCl salt [FIG. 6]

General procedure for the synthesis of 2-(arylamino)thiazole-4-carboxylic acids (37a-d)

N-Aryl thiourea (0.01 mol) and ethyl bromopyruvate (0.011 mol) weredissolved in 3 mL ethanol and held at reflux for 2 h. The reaction wascooled, the crystalline ethyl 2-(substituted phenylamino)thiazole-4-carboxylate were collected by filtration and washed withethanol. Refluxing the mixture of ethyl esters with the NaOH-ethanolsolution gave final compounds 73a-d which were used directly in the nextsteps.

N-Methoxy-N-methyl-2-(arylamino)thiazole-4-carboxamides (74a-d)

were synthesized using the same method as used for 38d (see Example 1,FIG. 2).

N-Methoxy-N-methyl-2-(phenylamino)thiazole-4-carboxamide (74a)

90.2% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.39 (s, 2H), 7.38 (br, 1H),7.36-7.33 (m, br, 4H), 7.09 (t, br, 1H), 3.77 (s, 3H), 3.43 (s, 3H),2.33 (s, 3H). MS (ESI) m/z 286.0 (M+Na)⁺.

N-Methoxy-N-methyl-2-(p-tolylamino)thiazole-4-carboxamide (74b)

93.3% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.35 (s, 1H), 7.31 (br, 1H), 7.22(d, 2H), 7.16 (d, 2H), 3.76 (s, 3H), 3.42 (s, 3H), 2.33 (s, 3H). MS(ESI) m/z 278.0 (M+H)⁺.

2-(4-Fluorophenylamino)-N-methoxy-N-methylthiazole-4-carboxamide (74c)

89.7% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.36 (s, 1H), 7.36-7.31 (m, 2H),7.07-7.04 (m, 6H), 3.76 (s, 3H), 3.42 (s, 3H). MS (ESI) m/z 282.0(M+Na)⁺, 280.8 (M−H)⁻.

2-(4-Chlorophenylamino)-N-methoxy-N-methylthiazole-4-carboxamide (74d)

¹H NMR (500 MHz, CDCl₃) δ 7.66 (s, br, 1H), 7.41 (s, 1H), 7.34 (d, 2H),7.29 (d, 2H), 3.76 (s, 3H), 3.42 (s, 3H). MS: 295.8 (M−1)⁻; 320.0(M+Na)⁺.

General procedure for the synthesis of(2-(arylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanones (5a-d)

At −78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g,5.0 mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6mmol) under Ar₂ protection and stirred for 10 min. Weinreb amide 74a-d(1 mmol) in 10 mL THF was added to the lithium reagent and allowed tostir at RT for 2 hs. The reaction mixture was quenched with satd. NH₄Cl,extracted with ethyl ether, dried with MgSO₄. The solvent was removedunder reduced pressure to yield a crude product, which was purified bycolumn chromatography to obtain pure compound (5a-d).

(2-(Phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5a)

33.3% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 10.4 (s, 1H), 7.85 (s, 1H),7.68 (d, 2H, J=8.0 Hz), 7.31 (t, 2H, J=8.0 Hz), 6.98 (t, 1H, J=8.0 Hz),3.83 (s, 6H), 3.78 (s, 3H). MS (ESI) m/z 393.1 (M+H)⁺, 368.9 (M−H)⁻.

(2-(p-Tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5b)

40.6% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.48 (s, 1H), 7.47 (s, 2H), 7.30(br, 1H), 7.27 (d, 2H, J=8.5 Hz), 7.17 (d, 2H, J=8.5 Hz), 3.93 (s, 3H).3.90 (s, 6H), 2.34 (s, 3H). MS (ESI) m/z 385.1 (M+H)⁺, 382.9 (M−H)⁻.

(2-(p-Fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(5c)

39.6% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.52 (br, 1H), 7.49 (s, 1H), 7.45(s, 2H), 7.40-7.37 (q, 2H, J=4.5 Hz), 7.08-7.04 (t, 2H, J=8.0 Hz), 3.93(s, 3H), 3.89 (s, 6H). MS (ESI) m/z 389.3 (M+H)⁺, 386.9 (M−H)⁻.

(2-((4-Chlorophenyl)amino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(5d)

was prepared using the same method as used for 5a from1-(4-chlorophenyl)thiourea and ethyl bromopyruvate. Melting point:165-166° C. ¹H NMR (500 MHz, CDCl₃) δ 7.60 (s, br, 1H), 7.56 (s, 1H),7.47 (s, 2H), 7.38 (d, 2H), 7.31 (d, 2H), 3.94 (s, 3H), 3.89 (s, 6H).MS: 402.9 (M−1)⁻; 427.0 (M+Na)⁺.

General procedure for the synthesis of hydrochloride salts (5Ha-c)

At 0° C., to a solution of compound 5a-c (0.1 mmol) in 5 mL CH₂Cl₂ wasadded a solution of HCl in 1,4-dioxane (4 N, 2 mL) and stirred at RT forovernight. The precipitates 5Ha-c were collected and washed with diethylether.

(2-(Phenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Ha)

91.6% yield. ¹H NMR (500 MHz, DMSO-d₆) δ 12.9 (br, 1H), 7.49-7.46 (m,2H), 7.42-7.40 (m, 2H), 7.37-7.34 (m, br, 2H), 7.11 (s, 2H), 3.94 (s,3H), 3.92 (s, 6H). MS (ESI) m/z 389.1 (M+H)⁺.

(2-(p-Tolylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hb)

39.6% yield. ¹H NMR (500 MHz, CDCl₃) δ 7.30-7.25 (m, br, 5H), 7.12 (s,2H), 3.94 (s, 3H), 3.92 (s, 6H), 2.38 (s, 3H). MS (ESI) m/z 389.1(M+H)⁺.

(2-(p-Fluorophenylamino)thiazol-4-yl)(3,4,5-trimethoxyphenyl)methanonehydrochloride salt (5Hc)

89.3% yield. ¹H NMR (500 MHz, CDCl₃) δ 10.55 (s, 1H), 7.85 (s, 1H),7.72-7.69 (q, 2H, J=4.5 Hz), 7.50 (s, 2H), 7.18-7.15 (t, 2H, J=8.5 Hz),4.30 (br, 1H), 3.82 (s, 6H), 3.78 (s, 3H). MS (ESI) m/z 389.3 (M+H)⁺.

Synthesis of(2-(Phenylamino)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5e)

Scheme 1: Preparation of Compound 5e2,2-Diethoxy-N-(iminomethylene)ethanamine (a)

A solution of the aminoacetaldehyde diethyl acetal (5.32 g, 40 mmol) inether (20 mL) was added to a suspension of CNBr (4.22 g, 40 mmol) inhexane (20 mL) at RT. The reaction mixture was stirred at RT overnight.The solid was removed by filtration and washed with ether. The combinedfiltrate was concentrated. Flash chromatography of the concentratedresidue afforded 2.82 g (45%) of the N-(2,2-diethoxyethyl)carbodiimide(a). ¹H NMR (500 MHz, CDCl₃): 4.58 (t, J=5.5 Hz, 1H), 3.85 (br s, 1H),3.73 (m, 2H), 3.56 (m, 2H), 3.16 (J=5.5 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H),MS: 156.8 (M−H)⁻; 180.9 (M+Na)⁺.

1-(2,2-Diethoxyethyl)-3-phenylguanidine (b)

Aniline (1.66 g, 17.8 mmol) was dissolved in ethanol (25 mL), andN-(2,2-diethoxyethyl)carbodiimide (a), (2.82 g, 17.8 mmol), was addeddropwise. Then methanesulfonic acid (1.71 g, 17.8 mmol) was added, andthe mixture was warmed at reflux for 24 h. The reaction mixture waspoured into NaOH (0.5 M) and extracted with CH₂Cl₂. Drying andconcentration afforded a product that was subjected to flashchromatography to give the intermediate guanidine (b) (3.3 g, 73.8%). ¹HNMR (500 MHz, DMSO-d₆) δ 7.27-6.90 (m, 5H), 4.55 (t, 1H), 3.76-3.70 (m,2H), 3.60-3.54 (m, 2H), 3.35-3.34 (d, 2H), 1.22 (pent, 6H). MS: 249.8(M−H)⁻; 252.1 (M+H)⁺.

N-Phenyl-1H-imidazol-2-amine (c)

The guanidine (b) was dissolved in HCl (5 mL, 6 M) at 0° C. and thenstirred for 2 h. After the starting material was consumed, NaOH (25%)was added until a precipitate formed. This mixture was stirred for 30min. The reaction was then poured into NaOH (0.5 M), extracted withCH₂Cl₂, dried and concentrated. Flash chromatography afforded (c) (0.95g, 50%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (s, br, 1H), 7.34-6.74 (m,5H), 6.68 (s, 2H), 6.62 (br, 2H), 3.82 (s, 6H), 3.73 (s, 3H). MS: 157.6(M−H)⁻; 160.0 (M+H)⁺.

N-Phenyl-1-trityl-1H-imidazol-2-amine (d)

Trityl chloride (2.79 g, 10 mmol) was added to an ice-cooled solution ofphenyl amino imidazole (c) (1.59 g, 10 mmol) and triethylamine (1.01 g,10 mmol) in methylene dichloride (50 mL). The reaction mixture wasallowed to warm to RT and stirred overnight. The mixture was dilutedwith methylene dichloride, washed successively with H₂O, saturatedNaHCO₃, brine and dried with MgSO₄. Filtration and evaporation of thesolvent followed by chromatography separation gave the product (d). ¹HNMR (500 MHz, CDCl₃) δ 7.52-7.35 (m, 5H), 7.28-7.43 (m, 15H), 6.85 (s,2H), 6.41 (s, 1H), 6.08 (s, 1H). MS: 1399.8 (M−H)⁻; 402.8 (M+H)⁺.

(2-(Phenylamino)-1-trityl-1H-imidazol-4-yl)(3,4,5trimethoxyphenyl)methanone (e)

At −78° C., t-BuLi in THF (1.7 M, 0.34 mL, 0.58 mmol) was added to asolution of trityl protected compound (d) (116 mg, 0.289 mmol) in THF.Then 3,4,5-trimethoxybenzoyl chloride (66.5 mg, 0.289 mmol) was addedand stirred overnight. The reaction mixture was quenched with saturatedNH₄Cl, and dried with MgSO₄. Filtration and evaporation of the solventfollowed by chromatography afforded compound (e) (75 mg, 43.7%). ¹H NMR(500 MHz, CDCl₃) δ 7.55-7.41 (m, 5H), 7.32 (s, 1H), 7.28-7.18 (m, 15H),6.94 (s, 2H), 3.78 (s, 6H), 3.70 (s, 3H). MS: 594.2 (M−H)⁻; 596.3(M+H)⁺.

(2-(Phenylamino)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (5e)

To a solution of trityl protected compound (e) (50 mg, 0.084 mmol) inethyl ether was added 2 M HCl in ether (1 mL, 1 mmol). The reactionmixture was stirred overnight and washed with saturated NaHCO₃ and driedwith MgSO₄. Filtration and evaporation of the solvent followed by flashchromatography to yield de-protection compound 5e (18 mg, 63%). ¹H NMR(500 MHz, DMSO-d₆) δ 7.54 (s, br, 1H), 7.51-7.43 (m, 3H), 7.33 (d, 2H),7.04 (s, 2H), 6.62 (br, 2H) 3.82 (s, 6H), 3.73 (s, 3H). MS: 352.1(M−H)⁻; 354.3 (M+H)⁺.

Example 5 Synthesis of Selected Aryl-Benzoyl-Imidazole Compounds

Preparation of 2-aryl-4,5-dihydro-1H-imidazoles 14b, 14c, 14x (FIG. 7)

To a solution of appropriate benzaldehyde 8(b, c, x) (60 mmol) in t-BuOH(300 mL) was added ethylenediamine (66 mmol) and stirred for 30 min atRT. Potassium carbonate (75 mmol) and iodine (180 mmol) were added tothe reaction mixture sequentially followed by stirring at 70° C. for 3h. Sodium sulfite (Na₂SO₃) was added and the mixture was extracted bychloroform. The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(chloroform:methanol 20:1) to give a white solid. Yield: 50-60%.

Preparation of 2-aryl-1H-imidazoles (9a-j, p, x; FIGS. 7 and 8)

Method A (essential for only 9b, 9x FIG. 7): To a solution of2-aryl-4,5-dihydro-1H-imidazole 14b, x (35 mmol) in DMSO (100 mL) wasadded potassium carbonate

(38.5 mmol) and diacetoxyiodobenzene (38.5 mmol). The reaction mixturewas stirred overnight in darkness. Water was added followed byextraction with dichloromethane. The organic layer was dried overmagnesium sulfate and concentrated. The residue was subjected to flashcolumn chromatography (hexane:ethyl acetate 3:2) to give a white solid.Yield: 30%-50%.

Method B (essential for only 9c; FIG. 7): To a solution of2-aryl-4,5-dihydro-1H-imidazole 14c (50 mmol) in DMF (70 mL) was addedDBU (55 mmol) and CBrCl₃ (55 mmol). The reaction mixture was stirredovernight and a saturated NaHCO₃ (aqueous) solution was added followedby extraction with dichloromethane. The organic layer was dried overmagnesium sulfate and concentrated. The residue was subjected to flashcolumn chromatography (chloroform:methanol 50:1) to yield a white solid.Yield: 7%.

Method C (essential for 9a, 9d-j, 9p; FIG. 8): To a solution ofappropriate benzaldehyde (8a, 8d-j, 8p) (100 mmol) in ethanol (350 mL)at 0° C. was added a solution of 40% oxalaldehyde in water (12.8 mL, 110mmol) and a solution of 29% ammonium hydroxide in water (1000 mmol, 140mL). After stifling for 2-3 days at RT, the reaction mixture wasconcentrated and the residue was subjected to flash columnchromatography with dichloromethane as eluent to yield the titledcompound as a yellow powder. Yield: 20%-40%.

Preparation of 2-aryl-1-(phenylsulfonyl)-1H-imidazoles (10a-j, p, x;FIGS. 7 and 8)

To a solution of 2-aryl-1H-imidazole 9a-j, p, x (20 mmol) in anhydrousTHF (200 mL) at 0° C. was added sodium hydride (60% dispersion inmineral oil, 1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonylchloride (2.82 mL, 22 mmol) was added and the reaction mixture wasstirred overnight. After dilution by 100 mL of saturated NaHCO₃ solution(aqueous), the reaction mixture was extracted by ethyl acetate (500 mL).The organic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane:ethylacetate 2:1) to give a pale solid. Yield: 50%-70%.

Preparation of aryl(2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanones (11aa-ai, ba, ca,cb, da, db, ea, eb, fa, fb, ga, gb, ha, hb, ia, ib, ja, jb, pa; FIGS. 7and 8)

To a solution of 2-aryl-1-(phenylsulfonyl)-1H-imidazole (6.0 mmol)10a-j, p, x in anhydrous THF (30 mL) at −78° C. was added 1.7Mtert-butyllithium in pentane (5.3 mL, 9.0 mmol) and stirred for 10 min.Appropriate substituted benzoyl chloride (7.2 mmol) was added at −78° C.and stirred for overnight. The reaction mixture was diluted with 100 mLof saturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate(200 mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 4:1) to give a white solid. Yield: 15%-40%.

General procedure for the preparation of aryl(2-aryl-1H-imidazol-4-yl)methanones (12aa-ai, ba, ca, cb, da, db, ea,eb, fa, fb, ga, gb, ha, hb, ia, ib, ja, jb, pa; FIGS. 7 and 8)

To a solution of aryl(2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanones (2.0 mmol)11aa-ai, ba, ca, cb, da, db, ea, eb, fa, fb, ga, gb, ha, hb, ia, ib, ja,jb, pa in THF (20.0 mL) was added 1.0M tetrabutyl ammonium fluoride (4.0mmol) and stirred overnight. The reaction mixture was diluted by 50 mLof saturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate(100 mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 3:1) or recrystallized from water and methanol togive a white solid. Yield: 80-95%.

Preparation of (2-(4-hydroxyphenyl)-1H-imidazol-4-yl)(aryl)methanones(12ka, 12kb; FIG. 8)

To a solution of(2-(4-(benzyloxy)phenyl)-1H-imidazol-4-yl)(aryl)methanone 12ja or 12jb,(1 mmol) in AcOH (20 mL) was added concentrated HCl (2 mL) and refluxedovernight. After removing the solvent, the residue was recrystallizedfrom dichloromethane to give the titled compound as a yellow solid.Yield: 70-85%.

Preparation of(2-aryl-1H-imidazol-4-yl)(3,4,5-trihydroxyphenyl)methanones 13ea, 13fa,13ha (FIG. 8)

To a solution of aryl (2-aryl-1H-imidazol-4-yl)methanone 12ea, 12fa or12ha (0.5 mmol) in CH₂Cl₂ (6.0 mL) was added 1.0 M of BBr₃ (2 mmol) inCH₂Cl₂ and stirred for 1 h at RT. Water was added to destroy excessBBr₃. The precipitated solid was filtered and recrystallized from MeOHto afford a yellow solid. Yield: 60-80%.

Preparation of aryl (2-aryl-1H-imidazol-4-yl)methanone-HCl salt(12db-HCl)

To a solution of 12db (0.5 mmol) in methanol (20 mL) was added 2 Msolution of hydrogen chloride (5 mmol) in ethyl ether and stirredovernight at RT. The reaction mixture was concentrated and the residuewas washed by CH₂Cl₂ to yield the titled compound. Yield: 95%.

Preparation of aryl (2-phenyl-1H-imidazol-1-yl)methanone (12aba, 12aaa;FIG. 9)

To a solution of 2-phenyl-1H-imidazole 9a (10 mmol) in THF (20 mL) wasadded NaH (15 mmol) and substituted benzoyl chloride (12 mmol) at 0° C.The reaction mixture was stirred overnight and diluted by saturatedNaHCO₃ solution followed by extraction with ethyl acetate. The organiclayer was dried over magnesium sulfate and concentrated. The residue waspurified by flash column chromatography (chloroform) to give a whitesolid. Yield: 12-16%.

Preparation of 1-substituted-(2-phenyl-1H-imidazol-1-yl)-aryl-methanone(12dc, 12fc, 12daa, 12 dab, 12 cba, 11gaa, 12la; FIGS. 10-11)

The synthesis of 12dc, 12fc and 12daa, 12dab and 12cba is summarized inFIG. 10. Compounds 12da, 12cb and 12fa were synthesized according to thesynthesis described above and in FIGS. 7 and 8. Treatment of 12da and12fa with aluminum chloride provided the para-demethylated 12dc, 12fcwith the 3,5-dimethoxy being intact. Compound 12daa was prepared bybenzylation of the N−1 position of 12da. While methylation of the N−1position of 12da and 12cb afforded compounds 12dab and 12cba,respectively.

Synthesis of 12dc, 12fc, 12daa, 12dab, 12cba: Method D. (for 12dc and12fc) [FIG. 10]

R₁═CH₃  (12dc)

R₁═Cl  (12fc)

To a solution of 12da and 12fa (200 mg) in THF (20 mL) was addedaluminum chloride (10 equiv). The reaction mixture was stirredovernight. Water was added followed by extraction with ethyl acetate.The organic layer was dried over magnesium sulfate and concentrated. Theresidue was subjected to flash column chromatography (hexane:ethylacetate 1:1) to give a white-yellowish solid. Yield: 60%-80%.

Synthesis of 12daa, 12dab, 12cba, Method E: [FIG. 10]

R₁=Me; R₂=Bn; R₃=3,4,5-(OMe)₃  (12daa)

R₁=Me; R₂=CH₃; R₃=3,4,5-(OMe)₃  (12dab)

R₁=OMe; R₂=CH₃; R₃=F  (12cba)

To a solution of 12da and 12cb (100 mg) in THF (10 mL) in an ice-bathwas added sodium hydride (1.2 equiv) followed by the addition of methyliodide (for 12dab, 12cba) or benzyl bromide (for 12daa) (2 equiv). Theresulted reaction mixture was stirred for 5 h under reflux condition.After dilution by 50 mL of saturated NaHCO₃ solution (aqueous), thereaction mixture was extracted by ethyl acetate (100 mL). The organiclayer was dried over magnesium sulfate and concentrated. The residue waspurified by flash column chromatography (hexane:ethyl acetate 2:1) togive a white solid. Yield: 50%-98%. 12daa: Yield: 92.8%; mp 135-137° C.¹H NMR (CDCl₃, 500 MHz) δ 7.81 (s, 1H), 7.80 (d, J=6.5 Hz, 2H), 7.58 (d,J=8.0 Hz, 2H), 7.41-7.45 (m, 3H), 7.31-7.33 (m, 2H), 7.20 (d, J=7.0 Hz,2H), 5.33 (s, 2H), 3.99 (s, 3H), 3.98 (s, 6H), 2.47 (s, 3H). MS (ESI)calcd for C₂₇H₂₆N₂O₄ 442.2, found 443.1 [M+H]⁺. HPLC1: t_(R) 4.28 min,purity>99%.

Synthesis of 11gaa and 12la (FIG. 11)

R₁=N(Me)₂; R₂=(4-OMe)PhSO₂  (11gaa)

R₁=Br; R₂=H  (12la)

The substituted benzaldehyde compounds 8(l, g) were converted tocompounds 9(l, g) in the presence of ammonium hydroxide and glyoxal toconstruct the imidazole scaffold. The imidazole rings of compounds 9(l,g) were protected by an appropriate phenylsulfonyl group followed bycoupling with 3,4,5-trimethoxybenzoyl chloride to achieve compound11(la,gaa). Treatment of 11la with tert-butylammoniumfluoride to removethe protecting group afforded 12la.

Structural characterization of(1-Benzyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12daa) (FIG. 11)

Yield: 92.8%; mp 135-137° C. ¹H NMR (CDCl₃, 500 MHz) δ 7.81 (s, 1H),7.80 (d, J=6.5 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.41-7.45 (m, 3H),7.31-7.33 (m, 2H), 7.20 (d, J=7.0 Hz, 2H), 5.33 (s, 2H), 3.99 (s, 3H),3.98 (s, 6H), 2.47 (s, 3H). MS (ESI) calcd for C₂₇H₂₆N₂O₄ 442.2, found443.1 [M+Na]⁺. HPLC1: t_(R) 4.28 min, purity>99%.

Structural characterization of(2-(4-(dimethylamino)phenyl)-1-((4-methoxyphenyl)sulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(12gba)

Yield: 34.1%; mp 147-149° C. ¹H NMR (CDCl₃, 500 MHz) δ 8.07 (q, J=8.5Hz, 5.5 Hz, 2H), 7.78 (d, J=9.0 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.39(s, 1H), 7.23 (t, J=8.5 Hz, 2H), 6.91 (d, J=9.0 Hz, 2H), 6.68 (d, J=9.0Hz, 2H), 3.89 (s, 3H), 3.08 (s, 3H). MS (ESI) calcd for C₂₅H₂₂FN₃O₄S479.1, found 502.1 [M+Na]⁺. HPLC2: t_(R) 18.6 min, purity 96.9%.

Synthesis of(2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12la) (FIG. 11)

Synthesis of 9l, 9g:

To a solution of appropriate benzaldehyde (8l, and 8g, 100 mmol) inethanol (400 mL) at 0° C. was added a solution of 40% oxalaldehyde(glyoxal) in water (1.1 equiv) and a solution of 29% ammonium hydroxidein water (10 equiv). After stirring for 2-3 days at RT, the reactionmixture was concentrated and the residue was subjected to flash columnchromatography with dichloromethane as eluent to yield the titledcompound as a yellow powder. Yield: 10%-30%.

Synthesis of 10la, 10gb:

To a solution of imidazoles (9l, 9g) (10 mmol) in anhydrous THF (200 mL)at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.2equiv) and stirred for 20 min. 4-Methoxybenzenesulfonyl chloride (for10gb) or benzenesulfonyl chloride (for others)(1.2 equiv) was added andthe reaction mixture was stirred overnight. After dilution by 200 mL ofsaturated NaHCO₃ solution (aqueous), the reaction mixture was extractedby ethyl acetate (600 mL). The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by flash columnchromatography (hexane:ethyl acetate 2:1) to give a pale solid. Yield:40%-95%.

Synthesis of 11a, 11gaa:

To a solution of 2-aryl-1-(phenylsulfonyl)-1H-imidazole (10la, 10gb)(5.0 mmol) in anhydrous THF (30 mL) at −78° C. was added 1.7 Mtert-butyllithium in pentane (1.2 equiv) and stirred for 10 min.3,4,5-Trimethoxybenzoyl chloride (1.2 equiv) was added at −78° C. andstirred overnight. The reaction mixture was diluted with 100 mL ofsaturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate (300mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 3:1) to give a white solid. Yield: 5%-45%.

Synthesis of 12la:

To a solution of aryl(2-aryl-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone (11la), 2.0 mmol)in THF (25.0 mL) was added 1.0 M tetrabutyl ammonium fluoride (2 equiv)and stirred overnight. The reaction mixture was diluted by 60 mL ofsaturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate (150mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 4:1) or recrystallized from water and methanol togive a white solid. Yield: 80-98%.

Synthesis of(4-Fluorophenyl)(2-(4-methoxyphenyl)-1H-imidazol-4-yl)methanone (12cb)(FIG. 7)

To a solution of(4-fluorophenyl)(2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)methanone(11cb, 872 mg, 2.0 mmol) in THF (20.0 mL) was added 1.0 M tetrabutylammonium fluoride (4.0 mL, 4.0 mmol) and stirred overnight. The reactionmixture was diluted by 50 mL of saturated NaHCO₃ solution (aqueous) andextracted by ethyl acetate (100 mL). The organic layer was dried overmagnesium sulfate and concentrated. The residue was recrystallized fromwater and methanol to give a white solid. Yield: 90%; mp 245-247° C.

Synthesis of(2-(p-Tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (12da)(FIG. 8)

To a solution of(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11da, 492 mg, 1.0 mmol) in THF (15.0 mL) was added 1.0 M tetrabutylammonium fluoride (2.0 mL, 2.0 mmol) and stirred overnight. The reactionmixture was diluted by 30 mL of saturated NaHCO₃ solution (aqueous) andextracted by ethyl acetate (80 mL). The organic layer was dried overmagnesium sulfate and concentrated. The residue was recrystallized fromwater and methanol to give a white solid. Yield: 88.5%.

Synthesis of(2-(4-Chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa) (FIGS. 8 and 14)

2-(4-Chlorophenyl)-1H-imidazole (9f)

To a solution of 4-chlorobenzaldehyde (8f) (100 mmol) in ethanol (350mL) at 0° C. was added a solution of 40% oxalaldehyde in water (12.8 mL,110 mmol) and a solution of 29% ammonium hydroxide in water (1000 mmol,140 mL). After stifling for 2-3 days at RT, the reaction mixture wasconcentrated and the residue was subjected to flash columnchromatography with dichloromethane as eluent to yield the titledcompound as a yellow powder. Yield: 19.8%. ¹H NMR (500 MHz, DMSO-d₆) δ13.60 (br, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.27 (s,1H), 7.03 (s, 1H). MS (ESI): calculated for C₉H₇ClN₂, 178.0, found 178.9[M+H]⁺.

2-(4-Chlorophenyl)-1-(phenylsulfonyl)-1H-imidazole (10f)

To a solution of 2-(4-chlorophenyl)-1H-imidazole (9f) (20 mmol) inanhydrous THF (200 mL) at 0° C. was added sodium hydride (60% dispersionin mineral oil, 1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonylchloride (2.82 mL, 22 mmol) was added and the reaction mixture wasstirred overnight. After dilution by 100 mL of saturated NaHCO₃ solution(aqueous), the reaction mixture was extracted by ethyl acetate (500 mL).The organic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane:ethylacetate 2:1) to give a pale solid. Yield: 54.9%. ¹H NMR (500 MHz, CDCl₃)δ 7.65 (d, J=2.0 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.5 Hz,2H), 7.38 (t, J=8.0 Hz, 2H), 7.34-7.36 (m, 4H), 7.12 (d, J=1.5 Hz, 1H).MS (ESI): calculated for C₁₅H₁₁ClN₂O₂S, 318.0, found 341.0 [M+Na]⁺.

(2-(4-Chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11fa)

To a solution of 2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazole(10f) (6.0 mmol) in anhydrous THF (30 mL) at −78° C. was added 1.7 Mtert-butyllithium in pentane (5.3 mL, 9.0 mmol) and stirred for 10 min.3,4,5-Trimethoxybenzoyl chloride (7.2 mmol) was added at −78° C. andstirred for overnight. The reaction mixture was diluted with 100 mL ofsaturated NaHCO₃ solution (aqueous) and extracted by ethyl acetate (200mL). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography(hexane:ethyl acetate 4:1) to give a white solid. Yield: 36.8%; ¹H NMR(500 MHz, CDCl₃) δ 8.05 (d, J=7.5 Hz, 2H), 7.77 (t, J=7.5 Hz, 1H), 7.62(t, J=8.0 Hz, 2H), 7.48 (s, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.5Hz, 2H), 7.37 (s, 2H). MS (ESI): calculated for C₂₅H₂₁ClN₂O₆S, 512.1,found 513.1 [M+H]⁺.

(2-(4-Chlorophenyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(12fa)

To a solution of(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(11fa) (2.0 mmol) in THF (20.0 mL) was added 1.0 M tetrabutyl ammoniumfluoride (4.0 mmol) and stirred overnight. The reaction mixture wasdiluted by 50 mL of saturated NaHCO₃ solution (aqueous) and extracted byethyl acetate (100 mL). The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by flash columnchromatography (hexane:ethyl acetate 3:1) or recrystallized from waterand methanol to give a white solid. Yield: 80-95%. Yield: 36.9%; mp193-195° C. ¹H NMR (500 MHz, CDCl₃) δ 10.75 (br, 1H), 7.96 (d, J=8.5 Hz,2H), 7.83 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.23 (s, 2H), 3.97 (s, 3H),3.94 (s, 6H), 2.43 (s, 3H). MS (ESI): calculated for C₁₉H₁₇ClN₂O₄,372.1, found 395.1 [M+Na]⁺, 370.9 [M−H]⁻. HPLC Gradient: Solvent A(water) and Solvent B (methanol): 0-15 min 40-100% B (linear gradient),15-25 min 100% B: t_(R) 16.36 min, purity>99%.

Synthesis of(2-(4-Chlorophenyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone (12fb)(FIG. 8)

To a solution of(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H-imidazol-4-yl)(4-fluorophenyl)methanone(11fb, 440 mg, 1.0 mmol) in THF (12.0 mL) was added 1.0 M tetrabutylammonium fluoride (2.0 mL, 2.0 mmol) and stirred overnight. The reactionmixture was diluted by 20 mL of saturated NaHCO₃ solution (aqueous) andextracted by ethyl acetate (60 mL). The organic layer was dried overmagnesium sulfate and concentrated. The residue was recrystallized fromwater and methanol to give a white solid. Yield: 83.7%.

Physicochemical Characterization of Aryl-Benzoyl-Imidazole Compounds andIntermediates

Compound Physicochemical Cheracterization 2-phenyl-1H-imidazole (9a)Yield: 36.8%. ¹H NMR (500 MHz, DMSO- d₆) δ 12.52 (br, 1 H), 7.95 (d, J =7.0 Hz, 2 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.34 (t, J = 7.0 Hz, 1H),7.25-7.27. m, 1 H), 7.04-7.07. m, 1 H). MS (ESI): calculated for C₉H₈N₂,144.1, found 167.1 [M + Na]⁺. 2-(4-fluorophenyl)-1H-imidazole (9b)Yield: 56.5%. ¹H NMR (300 MHz, DMSO- d₆) δ 12.46 (br, 1 H), 7.94-7.99(m, 2 H), 7.24-7.30 (m, 2 H), 7.00-7.03 (m, 2 H). MS (ESI): calculatedfor C₉H₇FN₂, 162.1, found 163 [M + H]⁺, 160.6 [M − H]⁻.2-(4-methoxyphenyl)-1H-imidazole (9c) Yield: 22.2%. ¹H NMR (500 MHz,CDCl₃) δ 7.80 (d, J = 10.0 Hz, 2 H), 7.15 (s, 2 H), 3.86 (s, 3 H). MS(ESI): calculated for C₁₀H₁₀N₂O, 174.1, found 175 [M + H]⁺, 172.8 [M −H]⁻. 2-(p-tolyl)-1H-imidazole (9d) Yield: 36.1%. ¹H NMR (500 MHz, CDCl₃)δ 7.64 (d, J = 7.5 Hz, 2 H), 7.16 (d, J = 7.5 Hz, 2 H), 7.12 (s, 1 H),7.02 (s, 1 H). MS (ESI): calculated for C₁₀H₁₀N₂, 158.1, found 159.0[M + H]⁺, 156.8 [M − H]⁻. 2-(3,4,5-trimethoxyphenyl)-1H-imidazole (9e)Yield: 26.0%. ¹H NMR (500 MHz, CDCl₃) δ 7.26 (s, 2 H), 7.08 (d, J = 1.5Hz, 2 H), 3.86 (s, 3 H), 3.82 (s, 6 H). MS (ESI): calculated forC₁₂H₁₄N₂O₃, 234.1, found 234.9 [M + H]⁺. 2-(4-chlorophenyl)-1H-imidazole(9f) Yield: 19.8%. ¹H NMR (500 MHz, DMSO- d₆) δ 13.60 (br, 1 H), 7.94(d, J = 8.5 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.27 (s, 1 H), 7.03 (s,1 H). MS (ESI): calculated for C₉H₇ClN₂, 178.0, found 178.9 [M + H]⁺.4-(1H-imidazol-2-yl)-N,N-dimethylaniline (9g) Yield: 16.5%. ¹H NMR (300MHz, CDCl₃) δ 7.70 (dd, J = 7.0 Hz, 2.0 Hz, 2 H), 7.10 (s, 2 H), 6.75(dd, J = 9.0 Hz, 2.0 Hz, 2 H), 3.02 (s, 6 H). MS (ESI): calculated forC₁₁H₁₃N₃, 187.1, found 187.9 [M + H]⁺, 185.8 [M − H]⁻.2-(3,4-dimethoxyphenyl)-1H-imidazole (9h) Yield: 22.0%. ¹H NMR (500 MHz,CDCl₃) δ 7.52 (d, J = 1.5 Hz, 1 H), 7.27-7.28 (m, 1 H), 7.14 (s, 2 H),6.88 (d, J = 8.0 Hz, 1 H), 3.91 (s, 3 H), 3.87 (s, 3 H). MS (ESI):calculated for C₁₁H₁₂N₂O₂, 204.1, found 205.1 [M + H]⁺, 202.8 [M − H]⁻.2-(2-(trifluoromethyl)phenyl)-1H-imidazole Yield: 25.5%. ¹H NMR (500MHz, DMSO-d₆) (9i) δ 12.31 (br, 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.76(t, J = 8.0 Hz, 1 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.16 (br, 2 H). MS(ESI): calculated for C₁₀H₇F₃N₂, 212.1, found 212.9 [M + H]⁺, 210.7 [M −H]⁻. 2-(4-(benzyloxy)phenyl)-1H-imidazole (9j) Yield: 12.1%. ¹H NMR (500MHz, CDCl₃) δ 7.77 (d, J = 8.5 Hz, 2 H), 7.36-7.47 (m, 5 H), 7.10-7.18(m, 2 H), 7.06 (d, J = 9.0 Hz, 2 H), 5.13 (s, 2 H). MS (ESI): calculatedfor C₁₆H₁₄N₂O, 250.1, found 251.1 [M + H]⁺, 248.8 [M − H]⁻.2-(4-Bromophenyl)-1H-imidazole (9l) Yield: 19.5%. ¹H NMR (300 MHz,CDCl₃) δ 12.59 (s, 1 H), 7.87 (d, J = 8.1 Hz, 2 H), 7.64 (d, J = 8.1 Hz,1 H), 7.27 (s, 1 H), 7.04 (s, 1 H). MS (ESI) calcd for C₉H₇BrN₂ 222.0,found 222.8 [M + H]⁺. 2-(4-(Trifluoromethyl)phenyl)-1H-imidazole Yield:26.2%; ¹H NMR (500 MHz, CDCl₃) δ (9p) 8.03 (d, J = 8.0 Hz, 2 H), 7.66(d, J = 8.0 Hz, 2 H), 7.25 (s, 2 H). MS (ESI) calcd for C₁₀H₇F₃N₂ 212.1,found 213.1 [M + H]⁺. 2-(4-nitrophenyl)-1H-imidazole (9x) Yield: 53.7%.¹H NMR (500 MHz, DMSO-d₆) δ 12.97 (br, 1 H), 8.32 (d, J = 9.0 Hz, 2 H),8.17 (d, J = 9.0 Hz, 2 H), 7.42 (s, 1 H), 7.17 (s, 1H). MS (ESI):calculated for C₉H₇N₃O₂, 189.1, found 189.9 [M + H]⁺, 187.8 [M − H]⁻.2-phenyl-1-(phenylsulfonyl)-1H-imidazole Yield: 50.3%. ¹H NMR (500 MHz,CDCl₃) δ (10a) 7.64-7.67. (m, 1 H), 7.56 (t, J = 9.0 Hz, 1 H), 7.32-7.48(m, 9 H), 7.12-7.16 (m, 1 H). MS (ESI): calculated for C₁₅H₁₂N₂O₂S,284.1, found 307.1 [M + Na]⁺. 2-(4-fluorophenyl)-1-(phenylsulfonyl)-1H-Yield: 56.9%. ¹H NMR (500 MHz, CDCl₃) δ imidazole (10b) 7.66 (d, J = 2.0Hz, 1 H), 7.58 (t, J = 10.0 Hz, 1 H), 7.36-7.42 (m, 6 H), 7.12 (d, J =2.0 Hz, 1 H), 7.06 (t, J = 10.0 Hz, 2 H). MS (ESI): calculated forC₁₅H₁₁FN₂O₂S, 302.1, found 300.8 [M − H]⁻.2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H- Yield: 40.9%. ¹H NMR (500MHz, CDCl₃) δ imidazole (10c) 7.62 (d, J = 5.0 Hz, 1 H), 7.56 (tt, J =15.0 Hz, 5.0 Hz, 1 H), 7.32-7.43 (m, 6 H), 7.10 (d, J = 5.0 Hz, 1 H),6.88 (dt, J = 16.0 Hz, 6.0 Hz, 2 H), 3.87 (s, 3 H). MS (ESI): calculatedfor C₁₆H₁₄N₂O₃S, 314.1, found 337.1 [M + Na]⁺, 312.9 [M − H]⁻.1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazole Yield: 46.6%. ¹H NMR (500MHz, CDCl₃) δ (10d) 7.63 (d, J = 1.0 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.27-7.29 (m,2 H), 7.16 (d, J = 7.5 Hz, 2 H), 7.10 (s, 1 H), 2.41 (s, 3 H). MS (ESI):calculated for C₁₆H₁₄N₂O₂S, 298.1, found 321.1 [M + Na]⁺.1-(phenylsulfonyl)-2-(3,4,5- Yield: 55.7%. ¹H NMR (500 MHz, CDCl₃) δtrimethoxyphenyl)-1H-imidazole (10e) 7.68 (d, J = 1.5 Hz, 1 H), 7.55 (t,J = 7.0 Hz, 1 H), 7.42 (d, J = 7.5 Hz, 2 H), 7.35 (t, J = 8.5 Hz, 2 H),7.11 (d, J = 1.5 Hz, 2 H), 6.60 (s, 1 H), 3.90 (s, 3 H), 3.79 (s, 6 H).MS (ESI): calculated for C₁₈H₁₈N₂O₅S, 374.1, found 397.1 [M + Na]⁺.2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H- Yield: 54.9%. ¹H NMR (500 MHz,CDCl₃) δ imidazole (10f) 7.65 (d, J = 2.0 Hz, 1 H), 7.58 (t, J = 7.5 Hz,1 H), 7.43 (d, J = 8.5 Hz, 2 H), 7.38 (t, J = 8.0 Hz, 2 H), 7.34-7.36(m, 4 H), 7.12 (d, J = 1.5 Hz, 1 H). MS (ESI): calculated forC₁₅H₁₁ClN₂O₂S, 318.0, found 341.0 [M + Na]⁺.N,N-dimethyl-4-(1-(phenylsulfonyl)-1H- Yield: 48.3%. ¹H NMR (300 MHz,CDCl₃) δ imidazol-2-yl) aniline (10g) 7.59 (d, J = 2.0 Hz, 1 H), 7.55(t, J = 8.0 Hz, 1 H), 7.45 (d, J = 7.5 Hz, 2 H), 7.28-7.38 (m, 4 H),7.07 (d, J = 2.0 Hz, 1 H), 6.68 (d, J = 8.5 Hz, 2 H), 3.04 (s, 3 H). MS(ESI): calculated for C₁₇H₁₇N₃O₂S, 327.10, found 350.0 [M + Na]⁺, 325.9[M − H]⁻. 4-(1-((4-Methoxyphenyl)sulfonyl)-1H- Yield: 61.5%. ¹H NMR (500MHz, CDCl₃) δ imidazol-2-yl)-N,N-dimethylaniline (10gb) 7.58 (d, J = 1.5Hz, 1 H), 7.36 (t, J = 8.43 Hz, 4 H), 7.03-7.09 (m, 1 H), 6.80 (d, J =9.0 Hz, 2 H), 6.69 (d, J = 8.8 Hz, 2 H), 3.84 (s, 3 H), 3.05 (s, 6 H).MS (ESI): calculated for C₁₇H₁₇N₃O₂S, 327.1, found 358.2 [M + Na]⁺.2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)- Yield: 60.3%. ¹H NMR (500MHz, CDCl₃) δ 1H-imidazole (10h) 7.64 (d, J = 7.0 Hz, 1 H), 7.55 (t, J =7.5 Hz, 1 H), 7.40 (dd, J = 8.5 Hz, 1.5 Hz, 2 H), 7.35 (t, J = 8.0 Hz,2H), 7.09 (d, J = 2.0 Hz, 1 H), 7.02 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 6.89(d, J = 1.5 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3 H), 3.81 (s,3 H). MS (ESI): calculated for C₁₇H₁₆N₂O₄S, 344.10, found 367.0 [M +Na]⁺. 1-(phenylsulfonyl)-2-(2- Yield: 58.6%. ¹H NMR (500 MHz, CDCl₃) δ(trifluoromethyl)phenyl)-1H-imidazole (10i) 7.64-7.67 (m, 2 H),7.61-7.63 (m, 3 H), 7.40-7.46 (m, 5 H), 7.16 (d, J = 1.5 Hz, 1 H). MS(ESI): calculated for C₁₆H₁₁F₃N₂O₂S, 352.10, found 353.1 [M + H]⁺.2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)- Yield: 62.0%; mp 102-104° C.¹H NMR (500 MHz, 1H-imidazole (10j) CDCl₃) δ 7.56 (d, J = 1.0 Hz, 1 H),7.46 (t, J = 8.0 Hz, 1 H), 7.20-7.40 (m, 11 H), 7.03 (d, J = 1.0 Hz,1H), 6.89 (t, J = 8.0 Hz, 2 H), 5.08 (s, 2 H). MS (ESI): calculated forC₂₂H₁₈N₂O₃S, 390.10, found 413.1 [M + Na]⁺. HPLC2: t_(R) 18.22 min,purity 95.9%. 2-(4-Bromophenyl)-1-(phenylsulfonyl)-1H- Yield: 61.2%. ¹HNMR (500 MHz, CDCl₃) δ imidazole (10la) 7.71 (d, J = 2.0 Hz, 1 H), 7.64(t, J = 7.0 Hz, 1 H), 7.57 (d, J = 9.0 Hz, 2 H), 7.49 (d, J = 7.0 Hz, 2H), 7.45 (t, J = 9.0 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 7.18 (d, J =1.5 Hz, 1 H). MS (ESI) calcd for C₁₅H₁₁BrN₂O₂S 362.0, found 363.0 [M +H]⁺. 1-(Phenylsulfonyl)-2-(4- Yield: 36.7%; ¹H NMR (500 MHz, CDCl₃) δ(trifluoromethyl)phenyl)-1H-imidazole (10p) 7.75 (d, J = 2.0 Hz, 1 H),7.69 (d, J = 8.0 Hz, 2 H), 7.65 (t, J = 8.0 Hz, 1 H), 7.60 (d, J = 8.0Hz, 2 H), 7.48 (d, J = 7.5 Hz, 2 H), 7.43 (t, J = 8.0 Hz, 2 H), 7.22 (d,J = 2.0 Hz, 1 H). MS (ESI) calcd for C₁₆H₁₁F₃N₂O₂S 352.1, found 553.1[M + H]⁺. 2-(4-nitrophenyl)-1-(phenylsulfonyl)-1H- Yield: 50%; mp145-147° C. ¹H NMR (500 MHz, imidazole (10x) DMSO-d₆) δ 8.28 (d, J = 8.5Hz, 2 H), 8.03 (d, J = 1.5 Hz, 1 H), 7.78 (t, J = 7.5 Hz, 1 H),7.64-7.68 (m, 4H), 7.60 (t, J = 8.0 Hz, 2 H), 7.30 (d, J = 1.5 Hz, 1 H).MS (ESI): calculated for C₁₅H₁₁N₃O₄S, 329.10, found 352.0 [M + Na]⁺,327.9 [M − H]⁻. HPLC2: t_(R) 14.87 min, purity 98.8%.(4-methoxyphenyl)(2-phenyl-1- Yield: 26.3%; mp 118-120° C. ¹H NMR (500MHz, (phenylsulfonyl)-1H-imidazol-4-yl)methanone DMSO-d₆) δ 8.37 (d, J =1.0 Hz, 1 H), (11ab) 8.15-8.18 (m, 2 H), 8.12 (d, J = 9.0 Hz, 2 H),7.56-7.64 (m, 5 H), 7.46-7.50 (m, 3 H), 7.16 (d, J = 8.0 Hz, 2 H), 3.90(s, 3 H). MS (ESI): calculated for C₂₃H₁₈N₂O₄S, 418.10, found 419.1 [M +H]⁺. HPLC2: t_(R) 17.72 min, purity 95.7%. (3-methoxyphenyl)(2-phenyl-1-Yield: 31.2%; mp 136-138° C. ¹H NMR (500 MHz,(phenylsulfonyl)-1H-imidazol-4-yl)methanone CDCl₃) δ 8.35 (s, 1 H), 7.86(d, J = 8.0 Hz, (11ac) 1 H), 7.72 (s, 1 H), 7.60 (t, J = 7.5 Hz, 1 H),7.51 (t, J = 7.5 Hz, 1 H), 7.35-7.42 (m, 9H), 7.14 (dd, J = 8.0 Hz, 2.0Hz, 1 H), 3.88 (s, 3 H). MS (ESI): calculated for C₂₃H₁₈N₂O₄S, 418.10,found 419.1 [M + H]⁺. HPLC2: t_(R) 17.72 min, purity 95.7%.(2-phenyl-1-(phenylsulfonyl)-1H-imidazol-4- Yield: 28.9%; mp 108-110° C.¹H NMR (500 MHz, yl)(p-tolyl)methanone (11ah) CDCl₃) δ 8.00 (d, J = 7.5Hz, 2 H), 7.98 (q, J = 8.0 Hz, 1.5 Hz, 2 H), 7.91 (d, J = 8.0 Hz, 1 H),7.81 (s, 1 H), 7.44-7.48 (m, 3 H), 7.35-7.40 (m, 2 H), 7.30 (t, J = 8.0Hz, 2 H), 7.20 (s, 2 H), 2.42 (s, 3 H). MS (ESI): calculated forC₂₃H₁₈N₂O₃S, 402.10, found 403.1 [M + H]⁺. HPLC2: t_(R) 16.06 min,purity 96.2%. (4-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)- Yield:25.4%; mp 114-116° C. ¹H NMR (500 MHz, 1H-imidazol-4-yl)methanone(11af)CDCl₃) δ 8.10 (q, J = 3.5 Hz, 5.5 Hz, 2 H), 7.88 (d, J = 7.5 Hz, 2 H),7.67 (t, J = 7.5 Hz, 1 H), 7.48-7.54 (m, 3 H), 7.38-7.41 (m, 5 H), 7.24(t, J = 8.5 Hz, 2 H). MS (ESI): calculated for C₂₂H₁₅FN₂O₃S, 406.10,found 429.1 [M + Na]⁺. HPLC2: t_(R) 15.43 min, purity 96.1%.(3-fluorophenyl)(2-phenyl-1-(phenylsulfonyl)- Yield: 18.3%; mp 102-104°C. ¹H NMR (500 MHz, 1H-imidazol-4-yl)methanone(11ag) CDCl₃) δ 8.14 (d, J= 7.5 Hz, 1 H), 7.76-7.87 (m, 3 H), 7.74 (d, J = 9.0 Hz, 1 H), 7.37-7.57(m, 10 H), 7.38-7.41 (m, 5 H), 7.24 (t, J = 8.5 Hz, 2 H). MS (ESI):calculated for C₂₂H₁₅FN₂O₃S, 406.10, found 429.1 [M + Na]⁺. HPLC2: t_(R)15.75 min, purity 96.5%. (4-fluorophenyl)(2-(4-methoxyphenyl)-1- Yield:23.5%; mp 135-137° C. ¹H NMR (500 MHz,(phenylsulfonyl)-1H-imidazol-4-yl)methanone CDCl₃) δ 8.00 (d, J = 5.5Hz, 2 H), (11cb) 7.74-7.76 (m, 2 H), 7.54-7.58 (m, 1 H), 7.40 (d, J =7.0 Hz, 2 H), 7.28-7.30 (m, 3 H), 7.14-7.16 (m, 2 H), 6.80-6.82 (m, 2H), 3.80 (s, 3 H). MS (ESI): calculated for C₂₃H₁₇FN₂O₄S, 436.10, found459.0 [M + Na]⁺, 434.9 [M − H]⁻. HPLC2: t_(R) 16.53 min, Purity 96.1%.(1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol- Yield: 33.8%; ¹H NMR (500MHz, CDCl₃) δ 4-yl)(3,4,5-trimethoxyphenyl)methanone 8.00 (d, J = 8.0Hz, 2 H), 7.70 (t, J = 7.5 Hz, 1 (11da) H), 7.55 (t, J = 8.0 Hz, 2 H),7.44 (s, 2 H), 7.34 (s, 2H), 7.31 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0Hz, 2 H), 4.00 (s, 3 H), 3.98 (s, 6 H). MS (ESI): calculated forC₂₆H₂₄N₂O₆S, 492.14, found 515.2 [M + Na]⁺.(4-fluorophenyl)(1-(phenylsulfonyl)-2-(p- Yield: 18.6%; mp 142-144° C.¹H NMR (500 MHz, tolyl)-1H-imidazol-4-yl)methanone (11db) CDCl₃) δ 8.07(q, J = 8.5 Hz, 5.5 Hz, 2 H), 7.88 (d, J = 7.5 Hz, 2 H), 7.64 (t, J =8.0 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 2 H), 7.38 (s, 1H), 7.30 (d, J = 8.0Hz, 2 H), 7.18-7.24 (m, 4 H), 2.43 (s, 3 H). MS (ESI): calculated forC₂₃H₁₇FN₂O₃S, 420.10, found 443.0 [M + Na]⁺, 418.9 [M − H]⁻. HPLC2:t_(R) 17.28 min, purity 97.3%. (1-(phenylsulfonyl)-2-(3,4,5- Yield:21.1%; mp 135-137° C. ¹H NMR (500 MHz,trimethoxyphenyl)-1H-imidazol-4-yl)(3,4,5- CDCl₃) δ 7.91 (d, J = 8.0 Hz,2 H), 7.65 (t, trimethoxyphenyl)methanone (11ea) J = 7.5 Hz, 1 H), 7.51(t, J = 8.0 Hz, 2 H), 7.44 (s, 1 H), 7.34 (s, 2 H), 6.60 (s, 2 H), 3.98(s, 3 H), 3.96 (s, 6 H), 3.91 (s, 3 H), 3.73 (s, 6 H). MS (ESI):calculated for C₂₈H₂₈N₂O₉S, 568.2, found 569.2 [M + H]⁺. HPLC1: t_(R)17.86 min, purity 98.9%. (4-fluorophenyl)(1-(phenylsulfonyl)-2-(3,4,5-Yield: 18.8%; mp 135-137° C. ¹H NMR (500 MHz,trimethoxyphenyl)-1H-imidazol-4- CDCl₃) δ 8.11 (q, J = 5.5 Hz, 3.0 Hz, 1yl)methanone (11eb) H), 8.00-8.03 (m, 1 H), 7.82 (d, J = 7.5 Hz, 1 H),7.78 (s, 1 H), 7.64 (t, J = 7.0 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H),7.42 (s, 1 H), 7.21-7.26 (m, 4 H), 6.62 (s, 1 H), 3.98 (s, 3 H), 3.96(s, 6 H), 3.93 (s, 3 H). MS (ESI): calculated for C₂₅H₂₁FN₂O₆S, 496.10,found 497.1 [M + H]⁺. HPLC2: t_(R) 15.26 min, purity 98%.(2-(4-chlorophenyl)-1-(phenylsulfonyl)-1H- Yield: 36.8%; mp 153-155° C.¹H NMR (500 MHz, imidazol-4-yl)(4-fluorophenyl)methanone CDCl₃) δ 8.06(q, J = 5.5 Hz, 3.0 Hz, 2 H), (11fb) 7.89 (d, J = 7.5 Hz, 2 H), 7.68 (t,J = 8.0 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 2 H), 7.34-7.38 (m, 5H), 7.23 (t,J = 8.5 Hz, 2 H). MS (ESI): calculated for C₂₂H₁₄ClFN₂O₃S, 440.0, found463.0 [M + Na]⁺. HPLC2: t_(R) 17.72 min, purity 97.38%.(2-(4-(dimethylamino)phenyl)-1- Yield: 32.2%; mp 157-159° C. ¹H NMR (500MHz, (phenylsulfonyl)-1H-imidazol-4-yl)(3,4,5- CDCl₃) δ 7.89 (d, J = 8.0Hz, 2 H), 7.62 (t, trimethoxyphenyl)methanone (11ga) J = 7.5 Hz, 1 H),7.48 (t, J = 8.0 Hz, 2 H), 7.43 (s, 1 H), 7.32 (d, J = 8.5 Hz, 2 H),7.30 (s, 2H), 6.62 (d, J = 9.0 Hz, 2 H), 3.97 (s, 3 H), 3.95 (s, 6 H),3.05 (s, 6 H). MS (ESI): calculated for C₂₇H2₇N₃O₆S, 521.2, found 544.1[M + Na]⁺, 519.8 [M − H]⁻. HPLC2: t_(R) 16.00 min, purity 97.9%.(2-(4-(dimethylamino)phenyl)-1- Yield: 38.5%; mp 125-127° C. ¹H NMR (500MHz, (phenylsulfonyl)-1H-imidazol-4-yl)(4- CDCl₃) δ 8.04 (q, J = 5.5 Hz,3.5 Hz, 2 H), fluorophenyl)methanone (11gb) 7.80 (d, J = 7.5 Hz, 2 H),7.61 (t, J = 8.0 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 2 H), 7.39 (s, 1 H),7.35 (d, J = 9.0 Hz, 2 H), 7.21 (t, J = 8.5 Hz, 2 H), 6.62 (d, J = 9.0Hz, 2 H), 3.05 (s, 6 H). MS (ESI): calculated for C₂₄H₂₀FN₃O₃S, 449.10,found 472.1 [M + Na]⁺, 447.9 [M − H]⁻. HPLC2: t_(R) 16.85 min, purity96.5%. (2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)- Yield: 28.6%; mp136-138° C. ¹H NMR (300 MHz, 1H-imidazol-4-yl)(3,4,5- CDCl₃) δ 7.92 (dd,J = 8.5 Hz, 1.5 Hz, 2 trimethoxyphenyl)methanone (11ha) H), 7.66 (t, J =7.5 Hz, 2 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.43 (s, 1 H), 7.33 (s, 2 H),7.02 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 6.91 (d, J = 2.0 Hz, 1 H), 6.86 (d,J = 8.5 Hz, 1 H), 3.98 (s, 3 H), 3.96 (s, 9 H), 3.77 (s, 3 H). MS (ESI):calculated for C₂₇H₂₆N₂O₈S, 538.10, found 561.1 [M + Na]⁺, 536.8 [M −H]⁻. HPLC2: t_(R) 14.67 min, purity 98.2%.(2-(3,4-dimethoxyphenyl)-1-(phenylsulfonyl)- Yield: 31.9%; mp 144-145°C. ¹H NMR (300 MHz, 1H-imidazol-4-yl)(4-fluorophenyl)methanone CDCl₃) δ8.09 (q, J = 5.5 Hz, 3.5 Hz, 2 (11hb) H), 7.81 (d, J = 8.0 Hz, 2 H),7.62 (t, J = 7.5 Hz, 2 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.40 (s, 1 H),7.21-7.25 (m, 2 H), 7.04 (dd, J = 8.0 Hz, 2.0 Hz, 1 H), 6.92 (d, J = 2.0Hz, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 3.96 (s, 3 H), 3.79 (s, 6 H). MS(ESI): calculated for C₂₄H₁₉FN₂O₅S, 466.10, found 489.1 [M + Na]⁺, 464.8[M − H]⁻. HPLC2: t_(R) 15.52 min, purity 97.4%.(1-(phenylsulfonyl)-2-(2- Yield: 25.0%; mp 155-157° C. ¹H NMR (500 MHz,(trifluoromethyl)phenyl)-1H-imidazol-4- DMSO-d₆) δ 7.91 (d, J = 8.0 Hz,1 H), yl)(3,4,5-trimethoxyphenyl)methanone (11ia) 7.84 (q, J = 7.5 Hz,5.0 Hz, 2 H), 7.77-7.80 (m, 2 H), 7.75 (s, 2 H), 7.66 (t, J = 8.0 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1 H), 7.18 (s, 2 H), 3.87 (s, 6 H), 3.81 (s, 3H). MS (ESI): calculated for C₂₆H₂₁F₃N₂O₆S, 546.10, found 569.0 [M +Na]⁺. HPLC2: t_(R) 16.16 min, purity 98.9%. (1-(phenylsulfonyl)-2-(2-Yield: 25.0%; mp 151-153° C. ¹H NMR (500 MHz,(trifluoromethyl)phenyl)-1H-imidazol-4-yl)(4- CDCl₃) δ 8.03 (q, J = 5.5Hz, 3.0 Hz, 2 fluorophenyl)methanone (11ib) H), 7.90 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 1 H), 7.69 (q, J = 7.0 Hz, 6.5 Hz, 2 H), 7.61(t, J = 8.0 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 2 H), 7.34-7.36 (m, 2 H),7.23 (t, J = 8.5 Hz, 2 H). MS (ESI): calculated for C₂₃H₁₄F₄N₂O₃S,474.10, found 497.0 [M + Na]⁺. HPLC2: t_(R) 16.80 min, purity 98.2%.(2-(4-(benzyloxy)phenyl)-1-(phenylsulfonyl)- Yield: 22.3.0%; mp 149-151°C. ¹H NMR 1H-imidazol-4-yl)(4-fluorophenyl)methanone (500 MHz, CDCl₃) δ8.09 (q, J = 5.5 Hz, 3.5 Hz, (11jb) 2 H), 7.82 (d, J = 7.5 Hz, 2 H),7.63 (t, 7.5 Hz, 1 H), 7.36-7.50 (m, 10 H), 7.25 (t, J = 8.5 Hz, 2 H),6.98 (d, J = 8.0 Hz, 2 H), 5.17 (s, 2 H). MS (ESI): calculated forC₂₉H₂₁FN₂O₄S, 512.10, found 535.0 [M + Na]⁺. HPLC2: t_(R) 18.35 min,purity 95.1%. (2-(4-bromophenyl)-1-(phenylsulfonyl)-1H- Yield: 32.6% ¹HNMR (500 MHz, CDCl₃) δ imidazol-4-yl)(3,4,5- 8.06 (d, J = 8.0 Hz, 2 H),7.88 (d, J = 8.5 Hz, 1 trimethoxyphenyl)methanone (11la) H), 7.77 (t, J= 7.0 Hz, 1 H), 7.54-7.63 (m, 4 H), 7.31-7.36 (m, 4 H), 4.04 (s, 3 H),4.01 (s, 6 H). MS (ESI) calcd for C₂₅H₂₁BrN₂O₆S 556.0, found 557.0 [M +H]⁺. (1-(phenylsulfonyl)-2-(4- Yield: 36.7%; ¹H NMR (500 MHz, CDCl₃) δ(trifluoromethyl)phenyl)-1H-imidazol-4- 8.06 (d, J = 7.5 Hz, 2 H), 7.78(t, J = 8.0 Hz, 1 yl)(3,4,5-trimethoxyphenyl)methanone (11pa) H), 7.72(d, J = 8.0 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2H), 7.50 (s, 1 H), 7.37 (s, 2 H), 4.04 (s, 3 H), 4.02 (s, 6 H). MS (ESI)calcd for C₂₆H₂₁F₃N₂O₆S 546.1, found 547.1 [M + H]⁺.(2-(4-(dimethylamino)phenyl)-1-((4- Yield: 34.1%; mp 147-149° C. ¹H NMR(500 MHz, methoxyphenyl)sulfonyl)-1H-imidazol-4- CDCl₃) δ 8.07 (q, J =8.5 Hz, 5.5 Hz, 2 yl)(3,4,5-trimethoxyphenyl)methanone H), 7.78 (d, J =9.0 Hz, 2 H), 7.41 (d, J = 8.5 Hz, (11gaa) 2 H), 7.39 (s, 1 H), 7.23 (t,J = 8.5 Hz, 2 H), 6.91 (d, J = 9.0 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H),3.89 (s, 3 H), 3.08 (s, 3 H). MS (ESI) calcd for C₂₈H₂₉N₃O₇S 551.2,found 573.1 [M + Na]⁺. HPLC2: t_(R) 18.6 min, purity 96.9%.(2-phenyl-1H-imidazol-4-yl)(3,4,5- Yield: 10.1%; mp 227-229° C. ¹H NMR(500 MHz, trimethoxyphenyl)methanone (12aa) CDCl₃) δ 8.0-8.03 (m, 2 H),7.83 (s, 1 H), 7.34-7.38 (m, 3 H), 7.21 (s, 2 H), 3.90 (s, 3 H), 3.84(s, 6 H). MS (ESI): calculated for C₁₉H₁₈N₂O, 338.1, found 337.1 [M −H]⁻. HPLC2: t_(R)14.19 min, purity 96.3%.(4-methoxyphenyl)(2-phenyl-1H-imidazol-4- Yield: 16.6%; mp 179-181° C.¹H NMR (500 MHz, yl)methanone (12ab) CDCl₃) δ 11.1 (br, 1 H), 8.07-8.10(m, 2 H), 8.04 (d, J = 8.5 Hz, 2 H), 7.84 (d, J = 1.0 Hz, 1 H),7.49-7.51 (m, 3 H), 7.07 (d, J = 9.0 Hz, 2 H), 3.95 (s, 3 H). MS (ESI):calculated for C₁₇H₁₄N₂O₂, 278.10, found 279.0 [M + H]⁺. HPLC1: t_(R)15.14 min, purity >99%. (3-methoxyphenyl)(2-phenyl-1H-imidazol-4- Yield:22.5%; mp 160-162° C. ¹H NMR (500 MHz, yl)methanone (12ac) CDCl₃) δ 11.2(br, 1 H), 8.10-8.12 (m, 2 H), 7.87 (d, J = 1.0 Hz, 1 H), 7.61 (d, J =7.5 Hz, 1 H), 7.48-7.52 (m, 5 H), 7.21 (dd, J = 2.5 Hz, 8.5 Hz, 1 H),3.91 (s, 3 H). MS (ESI): calculated for C₁₇H₁₄N₂O₂, 278.10, found 279.0[M + H]⁺. HPLC2: t_(R) 15.07 min, purity >99%.(3,5-dimethoxyphenyl)(2-phenyl-1H- Yield: 26.2%; mp 168-170° C. ¹H NMR(500 MHz, imidazol-4-yl)methanone (12ad) CDCl₃) δ 8.04-8.06 (m, 2 H),7.88 (s, 1 H), 7.50-7.52 (m, 3 H), 7.15 (d, J = 2.0 Hz, 2 H), 6.75 (t, J= 1.0 Hz, 1 H), 3.89 (s, 6 H). MS (ESI): calculated for C₁₈H₁₆N₂O₃,308.10, found 331.1 [M + Na]⁺, 306.9 [M − H]⁻. HPLC2: t_(R) 15.59 min,purity >99%. (3,4-dimethoxyphenyl)(2-phenyl-1H- Yield: 18.6%; mp162-164° C. ¹H NMR (500 MHz, imidazol-4-yl)methanone (12ae) CDCl₃) δ10.9 (br, 1 H), 8.05 (dd, J = 1.5 Hz, 8.0 Hz, 2 H), 7.86 (d, J = 1.5 Hz,1 H), 7.74 (dd, J = 2.0 Hz, 8.5 Hz, 1 H), 7.56 (d, J = 2.0 Hz, 1 H),7.50-7.52 (m, 3 H), 7.04 (d, J = 8.5 Hz, 1 H), 4.03 (s, 3 H), 3.99 (s, 3H). MS (ESI): calculated for C₁₈H₁₆N₂O₃, 308.10, found 331.1 [M + Na]⁺,306.9 [M − H]⁻. HPLC2: t_(R) 13.54 min, purity >99%.(4-fluorophenyl)(2-phenyl-1H-imidazol-4- Yield: 30.2%; mp 231-233° C. ¹HNMR (500 MHz, yl)methanone (12af) CDCl₃) δ 10.6 (br, 1 H), 8.02-8.05 (m,4 H), 7.81 (d, J = 1.0 Hz, 1 H), 7.51-7.54 (m, 3 H), 7.27 (t, J = 8.5Hz, 2 H). MS (ESI): calculated for C₁₆H₁₁FN₂O, 266.10, found 267.0 [M +H]⁺, 264.8 [M − H]⁻. HPLC1: t_(R) 15.37 min, purity 98.9%.(3-fluorophenyl)(2-phenyl-1H-imidazol-4- Yield: 23.4%; mp 212-214° C. ¹HNMR (500 MHz, yl)methanone (12ag) CDCl₃) δ 8.05 (dd, J = 1.5 Hz, 7.5 Hz,2 H), 7.86 (s, 1 H), 7.84 (d, J = 7.0 Hz, 1 H), 7.74 (d, J = 8.5 Hz, 1H), 7.52-7.58 (m, 4 H), 7.37 (dt, J = 2.0 Hz, 6.0 Hz, 1 H). MS (ESI):calculated for C₁₆H₁₁FN₂O, 266.10, found 267.0 [M + H]⁺, 264.8 [M − H]⁻.HPLC1: t_(R) 15.29 min, purity >99%. (2-phenyl-1H-imidazol-4-yl)(p-Yield: 15.6%; mp 225-227° C. ¹H NMR (500 MHz, tolyl)methanone (12ah)CDCl₃) δ 11.1 (br, 1 H), 8.08 (d, J = 7.5 Hz, 2 H), 7.93 (d, J = 9.0 Hz,2 H), 7.84 (s, 1 H), 7.48-7.52 (m, 3 H), 7.38 (d, J = 10.0 Hz, 2 H),2.50 (s, 3 H). MS (ESI): calculated for C₁₇H₁₄N₂O, 262.10, found 263.0[M + H]⁺, 260.8 [M − H]⁻. HPLC2: t_(R) 15.86 min, purity 98.7%.(2-phenyl-1H-imidazol-4-yl)(m- Yield: 20.5%; mp 168-169° C. ¹H NMR (500MHz, tolyl)methanone (12ai) CDCl₃) δ 11.0 (br, 1 H), 8.09-8.11 (m, 2 H),7.84 (d, J = 1.5 Hz, 1 H), 7.81-7.82 (m, 2 H), 7.47-7.52 (m, 5 H), 2.50(s, 3 H). MS (ESI): calculated for C₁₇H₁₄N₂O, 262.10, found 285.0 [M +Na]⁺, 260.8 [M − H]⁻. HPLC2: t_(R) 15.89 min, purity >99%.(2-(4-fluorophenyl)-1H-imidazol-4-yl)(3,4,5- Yield: 12.2%. mp 176-178°C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone (12ba) CDCl₃) δ 10.72(br, 1 H), 8.02 (q, J = 5.0 Hz, 2 H), 7.84 (s, 1 H), 7.19 (t, J = 10.0Hz, 2 H), 4.00 (s, 6 H), 3.97 (s, 3 H). MS (ESI): calculated forC₁₉H₁₇FN₂O₄, 356.10, found 379.1 [M + Na]⁺, 354.9 [M − H]⁻. HPLC1: t_(R)17.23 min, purity >99% (2-(4-methoxyphenyl)-1H-imidazol-4- Yield: 10.2%;mp 220-222° C. ¹H NMR (300 MHz, yl)(3,4,5-trimethoxyphenyl)methanone(12ca) CDCl₃) δ 10.24 (br, 1 H), 7.93 (d, J = 14.5 Hz, 2 H), 7.81 (s, 1H), 7.24 (s, 2 H), 7.03 (d, J = 14.5 Hz, 2 H), 3.97 (s, 3 H), 3.95 (s, 6H), 3.90 (s, 3 H). MS (ESI): calculated for C₂₀H₂₀N₂O₅, 368.10, found391.0 [M + Na]⁺, 367.0 [M − H]⁻. HPLC2: t_(R) 14.46 min, purity 98.4%.(4-fluorophenyl)(2-(4-methoxyphenyl)-1H- Yield: 15.2%; mp 245-247° C. ¹HNMR (500 MHz, imidazol-4-yl)methanone (12cb) CDCl₃) δ 10.20 (br, 1 H),7.93-7.96 (m, 2 H), 7.85 (d, J = 5.0 Hz, 2 H), 7.68 (s, 1 H), 7.15-7.17(m, 2 H), 6.95 (d, J = 6.0 Hz, 2 H), 3.82 (s, 3 H). MS (ESI): calculatedfor C₁₇H₁₃FN₂O₂, 296.10, found 319.1 [M + Na]⁺, 294.9 [M − H]⁻. HPLC2:t_(R) 15.40 min, purity 98.8%. (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-Yield: 48.5%; mp 201-203° C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone(12da) CDCl₃) δ 10.40 (br, 1 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.82 (s, 1H), 7.31 (d, J = 8.0 Hz, 2 H), 7.24 (s, 2 H), 3.96 (s, 3 H), 3.94 (s, 6H), 2.43 (s, 3 H). MS (ESI): calculated for C₂₀H₂₀N₂O₄, 352.10, found375.2 [M + Na]⁺. HPLC2: t_(R) 15.45 min, purity 97.4%.(4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4- Yield: 56.3%; mp 229-231° C.¹H NMR (500 MHz, yl)methanone (12db) CDCl₃) δ 10.50 (br, 1 H), 7.99-8.02(m, 2 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.60 (d, J = 1.0 Hz, 1 H), 7.30 (d,J = 8.0 Hz, 2 H), 7.23 (t, J = 9.0 Hz, 2 H), 2.43 (s, 3 H). MS (ESI):calculated for C₁₇H₁₃FN₂O, 280.10, found 281.0 [M + H]⁺, 278.9 [M − H]⁻.HPLC2: t_(R) 16.31 min, purity >99%.(4-hydroxy-3,5-dimethoxyphenyl)(2-(p-tolyl)- Yield: 56.8%; mp 220-222°C. ¹H NMR (500 MHz, 1H-imidazol-4-yl)methanone (12dc) CDCl₃) δ 8.02 (d,J = 8.0 Hz, 2H), 7.91 (s, 1H), 7.39 (s, 2H), 7.28 (d, J = 7.5 Hz, 2H),4.00 (s, 6H), 2.44 (s, 3H). MS (ESI) calcd for C₁₉H₁₈FN₂O₄ 338.1, found339.1 [M + H]⁺. HPLC1: t_(R) 3.91 min, purity >99%.(3,4,5-trimethoxyphenyl)(2-(3,4,5- Yield: 86.8%; mp 196-198° C. ¹H NMR(500 MHz, trimethoxyphenyl)-1H-imidazol-4- DMSO-d₆) δ 13.3 (br, 0.47 H),13.50 (br, yl)methanone (12ea) 0.52 H), 8.19 (s, 0.49 H), 7.90 (s, 1 H),7.83 (s, 0.5 H), 7.59 (s, 1 H), 7.40 (s, 1 H), 7.18 (s, 1 H), 3.89 (s, 6H), 3.86 (s, 6 H), 3.77 (s, 3 H), 3.72 (s, 3 H). MS (ESI): calculatedfor C₂₂H₂₄N₂O₇, 428.2, found 451.1 [M + Na]⁺, 426.9 [M − H]⁻. HPLC2:t_(R) 14.49 min, purity >99%.(4-fluorophenyl)(2-(3,4,5-trimethoxyphenyl)- Yield: 90.2%; mp 153-155°C. ¹H NMR (500 MHz, 1H-imidazol-4-yl)methanone (12eb) CDCl₃) δ 10.42(br, 1 H), 8.00 (q, J = 5.5 Hz, 3.0 Hz, 2 H), 7.76 (s, 1 H), 7.23 (t, J= 8.5 Hz, 2 H), 7.19 (s, 2 H), 3.94 (s, 3 H), 3.92 (s, 3 H). MS (ESI):calculated for C₁₉H₁₇FN₂O₄, 356.1, found 379.0 [M + Na]⁺, 354.9 [M −H]⁻. HPLC2: t_(R) 15.31 min, purity >99%.(2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5- Yield: 36.9%; mp 193-195°C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone (12fa) CDCl₃) δ 10.75(br, 1 H), 7.96 (d, J = 8.5 Hz, 2 H), 7.83 (s, 1 H), 7.47 (d, J = 9.0Hz, 2 H), 7.23 (s, 2 H), 3.97 (s, 3 H), 3.94 (s, 6 H), 2.43 (s, 3 H). MS(ESI): calculated for C₁₉H₁₇ClN₂O₄, 372.1, found 395.1 [M + Na]⁺, 370.9[M − H]⁻. HPLC2: t_(R) 16.36 min, purity >99%.(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4- Yield: 83.7%; mp 232-234° C. ¹HNMR (500 MHz, fluorophenyl)methanone (12fb) CDCl₃) δ 10.78 (br, 1 H),8.00 (q, J = 5.5 Hz, 3.0 Hz, 2 H), 7.96 (d, J = 9.0 Hz, 2 H), 7.78 (s, 1H), 7.47 (d, J = 8.0 Hz, 2 H), 7.24 (t, J = 8.5 Hz, 2 H). MS (ESI):calculated for C₁₆H₁₀ClFN₂O, 300.1, found 323.0 [M + Na]⁺, 298.8 [M −H]⁻. HPLC2: t_(R) 17.08 min, purity >99%.(2-(4-chlorophenyl)-1H-imidazol-4-yl)(4- Yield: 80.2%; mp 216-218° C. ¹HNMR (500 MHz, hydroxy-3,5-dimethoxyphenyl)methanone CD₃OD) δ 8.06 (d, J= 8.5 Hz, 2 H), (12fc) 7.99 (s, 1 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.52(s, 2 H), 4.01 (s, 6 H). MS (ESI) calcd for C₁₈H₁₅ClN₂O₄ 358.1, found359.1 [M + H]⁺. HPLC2: t_(R) 4.12 min, purity >99%.(2-(4-(dimethylamino)phenyl)-1H-imidazol-4- Yield: 91.2%; mp 195-197° C.¹H NMR (500 MHz, yl)(3,4,5-trimethoxyphenyl)methanone (12ga) CDCl₃) δ10.39 (br, 1 H), 7.87 (d, J = 8.5 Hz, 2 H), 7.80 (s, 1 H), 7.23 (s, 2H), 6.75 (d, J = 9.0 Hz, 2 H), 3.95 (s, 3 H), 3.94 (s, 6 H), 3.05 (s, 6H). MS (ESI): calculated for C₂₁H₂₃N₃O₄, 381.2, found 404.2 [M + Na]⁺,380.0 [M − H]⁻. HPLC2: t_(R) 15.20 min, purity 95.8%.(2-(4-(dimethylamino)phenyl)-1H-imidazol-4- Yield: 86.7%; mp 278-280° C.¹H NMR (500 MHz, yl)(4-fluorophenyl)methanone (12gb) CDCl₃) δ 10.21 (br,1 H), 7.98 (q, J = 5.0 Hz, 3.5 Hz, 2 H), 7.84 (d, J = 8.5 Hz, 2 H), 7.72(s, 1 H), 7.20 (t, J = 8.5 Hz, 2 H), 6.76 (t, J = 9.0 Hz, 2 H), 3.06 (s,6 H). MS (ESI): calculated for C₁₈H₁₆FN₃O, 309.1, found 332.1 [M + Na]⁺,307.9 [M − H]⁻. HPLC2: t_(R) 16.06 min, purity 95.6%.(2-(3,4-dimethoxyphenyl)-1H-imidazol-4- Yield: 85.0%; mp 100-102° C. ¹HNMR (500 MHz, yl)(3,4,5-trimethoxyphenyl)methanone (12ha) CDCl₃) δ 10.19(br, 1 H), 7.81 (s, 1 H), 7.58 (d, J = 1.5 Hz, 1 H), 7.48 (d, J = 8.0Hz, 1 H), 7.25 (s, 2 H), 6.97 (d, J = 8.5 Hz, 1 H), 4.00 (s, 3 H), 3.96(s, 6 H), 3.95 (s, 6 H). MS (ESI): calculated for C₂₁H₂₂N₂O₆, 398.2,found 399.1 [M + H]⁺, 397.0 [M − H]⁻. HPLC2: t_(R) 13.73 min,purity >99%. (2-(3,4-dimethoxyphenyl)-1H-imidazol-4- Yield: 78.3%; mp174-176° C. ¹H NMR (500 MHz, yl)(4-fluorophenyl)methanone (12hb) CDCl₃)δ 8.02 (t, J = 9.0 Hz, 2 H), 7.75 (s, 1 H), 7.57 (s, 1 H), 7.48 (d, J =8.5 Hz, 1 H), 7.23 (t, J = 8.5 Hz, 2 H), 6.95 (d, J = 8.5 Hz, 1 H), 3.99(s, 3 H), 3.96 (s, 3 H). MS (ESI): calculated for C₁₈H₁₅FN₂O₃, 326.1,found 349.0 [M + Na]⁺, 324.9 [M − H]⁻. HPLC2: t_(R) 14.65 min,purity >99%. (2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4- Yield: 83.8%;mp 75-77° C. ¹H NMR (500 MHz, yl)(3,4,5-trimethoxyphenyl)methanone(12ia) CDCl₃) δ 10.37 (br, 1 H), 8.00-8.02 (m, 1 H), 7.87 (s, 1 H),7.82-7.85 (m, 1 H), 7.69-7.74 (m, 1 H), 7.62-7.66 (m, 1 H), 7.25 (s, 2H), 3.99 (s, 3 H), 3.98 (s, 6 H). MS (ESI): calculated for C₂₀H₁₇F₃N₂O₄,406.1, found 429.1 [M + Na]⁺, 405.0 [M − H]⁻. HPLC2: t_(R) 13.98 min,purity >99%. (4-fluorophenyl)(2-(2- Yield: 91.1%; mp 152-154° C. ¹H NMR(500 MHz, (trifluoromethyl)phenyl)-1H-imidazol-4- CDCl₃) δ 8.12-8.14 (m,2 H), 7.97 (d, J = 7.5 Hz, yl)methanone (12ib) 1 H), 7.82-7.85 (m, 2 H),7.69 (t, J = 7.5 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.22 (t, J = 9.0Hz, 2 H). MS (ESI): calculated for C₁₇H₁₀F₄N₂O, 334.1, found 357.1 [M +Na]⁺, 332.9 [M − H]⁻. HPLC2: t_(R) 15.10 min, purity >99%.(2-(4-(benzyloxy)phenyl)-1H-imidazol-4- Yield: 16.5%; mp 191-193° C. ¹HNMR (500 MHz, yl)(3,4,5-trimethoxyphenyl)methanone (12ja) CDCl₃) δ 10.22(br, 1 H), 7.93 (d, J = 9.0 Hz, 2 H), 7.81 (s, 1 H), 7.37-7.47 (m, 5 H),7.24 (s, 2 H), 7.11 (d, J = 8.5 Hz, 2 H), 5.16 (s, 2 H), 3.97 (s, 3 H),3.95 (s, 6 H). MS (ESI): calculated for C₂₆H₂₄N₂O₅, 444.2, found 467.1[M + Na]⁺, 442.9 [M − H]⁻. HPLC2: t_(R) 17.36 min, purity 95.5%.(2-(4-(benzyloxy)phenyl)-1H-imidazol-4- Yield: 84.7%; mp 212-214° C. ¹HNMR (300 MHz, yl)(4-fluorophenyl)methanone (12jb) CDCl₃) δ 10.28 (br, 1H), 799-8.04 (m, 2 H), 7.92-7.95 (m, 2 H), 7.76 (d, J = 1.5 Hz, 1 H),7.38-7.48 (m, 5 H), 7.20-7.25 (m, 2 H), 7.09-7.12 (m, 2 H), 5.16 (s, 2H). MS (ESI): calculated for C₂₃H₁₇FN₂O₂, 372.1, found 395.1 [M + Na]⁺.HPLC2: t_(R) 17.97 min, purity 97.8%.(2-(4-hydroxyphenyl)-1H-imidazol-4- Yield: 72.3%. mp 191-193° C. ¹H NMR(500 MHz, yl)(3,4,5-trimethoxyphenyl)methanone (12ka) CD₃OD) δ 8.31 (s,1 H), 7.90 (d, J = 8.5 Hz, 2 H), 7.31 (s, 2 H), 7.05 (s, 2 H), 3.95 (s,6 H), 3.88 (s, 3 H). MS (ESI): calculated for C₁₉H₁₈N₂O₅, 354.1, found355.1 [M + H]⁺, 352.9 [M − H]⁻. HPLC2: t_(R) 12.25 min, purity 98.7%.(2-(4-(hydroxyphenyl)-1H-imidazol-4-yl)(4- Yield: 89.0%; mp 276-278° C.¹H NMR (500 MHz, fluorophenyl)methanone (12kb) CDCl₃) δ 8.31 (s, 1 H),8.13 (q, J = 5.5 Hz, 3.0 Hz, 2 H), 7.93 (d, J = 8.5 Hz, 2 H), 7.38 (t, J= 8.5 Hz, 2 H), 7.07 (d, J = 8.5 Hz, 2 H). MS (ESI): calculated forC₁₆H₁₁FN₂O₂, 282.1, found 283.0 [M + H]⁺, 280.9 [M − H]⁻. HPLC2: t_(R)13.46 min, purity 97.65%. (2-(4-bromophenyl)-1H-imidazol-4-yl)(3,4,5-Yield: 25.6%; mp 190-192° C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone(12la) CDCl₃) δ 7.99 (d, J = 8.5 Hz, 2 H), 7.92 (s, 1 H), 7.70 (d, J =8.5 Hz, 2 H), 7.32 (s, 2 H), 4.03 (s, 3 H), 4.00 (s, 6 H). MS (ESI)calcd for C₁₉H₁₇BrN₂O₄ 416.0, found 417.0 [M + H]⁺. HPLC2: t_(R) 4.24min, purity 98.8%. (2-(4-(trifluoromethyl)phenyl)-1H-imidazol-4- Yield:85.3%; mp 195-196° C. ¹H NMR (500 MHz,yl)(3,4,5-trimethoxyphenyl)methanone (12pa) CDCl₃) δ 8.22 (d, J = 8.5Hz, 2 H), 7.96 (s, 1 H), 7.83 (d, J = 8.5 Hz, 2 H), 7.34 (s, 2 H), 4.04(s, 3 H), 4.00 (s, 6 H). MS (ESI) calcd for C₂₀H₁₇F₃N₂O₄ 406.1, found407.1 [M + H]⁺, HPLC2: t_(R) 18.00 min, purity >99%.(2-phenyl-1H-imidazol-1-yl)(3,4,5- Yield: 39.8%; mp 113-115° C. ¹H NMR(500 MHz, trimethoxyphenyl)methanone (12aaa) CDCl₃) δ 7.53 (q, J = 5.0Hz, 3.0 Hz, 2 H), 7.41 (d, J = 1.0 Hz, 1 H), 7.33-7.35 (m, 3 H), 7.23(d, J = 1.0 Hz, 1 H), 7.03 (s, 2 H), 3.93 (s, 3 H), 3.85 (s, 6 H). MS(ESI): calculated for C₁₉H₁₈N₂O₄, 338.1, found 339.1 [M + H]⁺. HPLC2:t_(R) 13.8 min, purity 95.6%. (4-methoxyphenyl)(2-phenyl-1H-imidazol-1-Yield: 56.3%; mp 68-70° C. ¹H NMR (500 MHz, yl)methanone (12aba) CDCl₃)δ 7.78 (d, J = 9.0 Hz, 2 H), 7.54-7.56 (m, 2 H), 7.32-7.34 (m, 4 H),7.21 (d, J = 1.0 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 2 H), 3.90 (s, 3 H). MS(ESI): calculated for C₁₇H₁₄N₂O₂, 278.1, found 301.0 [M + Na]⁺, 276.8 [M− H]⁻. HPLC2: t_(R) 14.72 min, purity 95.7%.(4-fluorophenyl)(2-(p-tolyl)-1H-imidazol-4- Yield: 95%; mp 115-117° C.¹H NMR (500 MHz, yl)methanone HCl salt (12db-HCl) DMSO-d₆) δ 8.20-8.23(m, 2 H), 8.18 (s, 1 H), 8.04 (d, J = 6.5 Hz, 2 H), 7.42 (t, J = 8.0 Hz,2 H), 7.37 (d, J = 7.0 Hz, 2 H), 2.38 (s, 3 H). MS (ESI): calculated forC₁₇H₁₄FClN₂O, 316.1, found 281.0 [M − HCl + H]⁺. HPLC2: t_(R) 17.16 min,purity >99%. (4-fluorophenyl)(2-(4-methoxyphenyl)-1- Yield: 90.2%; mp148-150° C. ¹H NMR (500 MHz, methyl-1H-imidazol-4-yl)methanone (12cba)CDCl₃) δ 8.45 (q, J = 8.5 Hz, 5.5 Hz, 2 H), 7.79 (s, 1 H), 7.63 (d, J =8.5 Hz, 2 H), 7.16 (t, J = 8.5 Hz, 2 H), 7.03 (d, J = 9.0 Hz, 2 H), 3.89(s, 3 H), 3.82 (s, 3 H). MS (ESI) calcd for C₁₈H₁₅FN₂O₂ 310.1, found311.0 [M + H]⁺. HPLC2: t_(R) 4.01 min, purity 97.6%.(1-benzyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5- Yield: 92.8%; mp 135-137°C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone (12daa) CDCl₃) δ 7.81 (s,1 H), 7.80 (d, J = 6.5 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.41-7.45(m, 3 H), 7.31-7.33 (m, 2 H), 7.20 (d, J = 7.0 Hz, 2 H), 5.33 (s, 2 H),3.99 (s, 3 H), 3.98 (s, 6 H), 2.47 (s, 3 H). MS (ESI) calcd forC₂₇H₂₆N₂O₄ 442.2, found 443.1 [M + Na]⁺. HPLC1: t_(R) 4.28 min,purity >99%. (1-methyl-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5- Yield:87.4%; mp 110-112° C. ¹H NMR (500 MHz, trimethoxyphenyl)methanone(12dab) CDCl₃) δ 7.87 (s, 2 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.65 (d, J =10 Hz, 2 H), 7.37 (d, J = 10 Hz, 2 H), 4.01 (s, 6 H), 4.00 (s, 3 H),3.90 (s, 3 H). MS (ESI) calcd for C₂₁H₂₂N₂O₄ 366.2, found 367.2 [M +H]⁺. HPLC1: t_(R) 4.23 min, purity >99%.(2-(4-(dimethylamino)phenyl)-1-((4- Yield: 34.1%; mp 147-149° C. ¹H NMRmethoxyphenyl)sulfonyl)-1H-imidazol-4- (CDCl₃, 500 MHz) δ 8.07 (q, J =8.5 Hz, 5.5 Hz, yl)(4-fluorophenyl)methanone (12gba) 2 H), 7.78 (d, J =9.0 Hz, 2 H), 7.41 (d, J = 8.5 Hz, 2 H), 7.39 (s, 1 H), 7.23 (t, J = 8.5Hz, 2 H), 6.91 (d, J = 9.0 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H), 3.89 (s,3 H), 3.08 (s, 3 H). MS (ESI) calcd for C₂₅H₂₂FN₃O₄S 479.1, found 502.1[M + Na]⁺. HPLC2: t_(R) 18.6 min, purity 96.9%.(3,4,5-trihydroxyphenyl)(2-(3,4,5- Yield: 66.1%. mp 294-296° C. ¹H NMR(500 MHz, trihydroxyphenyl)-1H-imidazol-4- CD₃OD) δ 8.07 (s, 1 H), 7.07(s, 2 H), yl)methanone (13ea) 7.02 (s, 2 H). MS (ESI): calculated forC₁₆H₁₂N₂O₇, 344.1, found 345.0 [M + H]⁺, 342.9 [M − H]⁻. HPLC2: t_(R)3.62 min, purity 97.9%. (2-(4-chlorophenyl)-1H-imidazol-4-yl)(3,4,5-Yield: 79.3%; mp >300° C. ¹H NMR (500 MHz, trihydroxyphenyl)methanone(13fa) CD₃OD) δ 8.02 (d, J = 8.5 Hz, 2 H), 7.77 (s, 1 H), 7.54 (d, J =8.5 Hz, 2 H), 7.14 (s, 2 H). MS (ESI): calculated for C₁₆H₁₁ClN₂O₄,330.0, found 331.1 [M + Na]⁺, 328.9 [M − H]⁻. HPLC2: t_(R) 11.9 min,purity 95.6%. (2-(3,4-dihydroxyphenyl)-1H-imidazol-4- Yield: 62.2%;mp >300° C. ¹H NMR (500 MHz, yl)(3,4,5-trihydroxyphenyl)methanone (13ha)CD₃OD) δ 8.11 (s, 1 H), 7.46 (d, J = 2.0 Hz, 1 H), 7.42 (dd, J = 8.5 Hz,2.0 Hz, 1 H), 7.10 (s, 2 H), 7.02 (d, J = 8.5 Hz, 1 H). MS (ESI):calculated for C₁₆H₁₂N₂O₆, 328.1, found 329.0 [M + H]⁺, 326.9 [M − H]⁻.HPLC2: t_(R) 3.64 min, purity 97.9%.2-(4-nitrophenyl)-4,5-dihydro-1H-imidazole Yield: 70.3%. ¹H NMR (500MHz, CDCl₃) δ (14x) 8.30 (d, J = 9.0 Hz, 2 H), 7.98 (d, J = 8.5 Hz, 2H), 3.88-3.95 (m, 4 H). MS (ESI): calculated for C₉H₉N₃O₂, 191.10, found191.9 [M + H]⁺, 189.7 [M − H]⁻.2-(4-fluorophenyl)-4,5-dihydro-1H-imidazole Yield: 60.2%. ¹H NMR (500MHz, CDCl₃) δ (14b) 7.80 (q, J = 7.0 Hz, 2 H), 7.11 (d, J = 10.0 Hz, 2H), 3.82 (br, 4 H). MS (ESI): calculated for C₉H₉FN₂, 164.10, found 165[M + H]⁺. 2-(4-methoxyphenyl)-4,5-dihydro-1H- Yield: 56.9%. ¹H NMR (500MHz, CDCl₃) δ imidazole (14c) 7.84 (d, J = 8.5 Hz, 2 H), 6.94 (d, J =9.0 Hz, 2 H), 3.87 (s, 3 H), 3.85 (br, 4 H). MS (ESI): calculated forC₁₀H₁₂N₂O, 176.10, found 177.0 [M + H]⁺.

Example 6 Synthesis of Selected Indolyl-Benzoyl-Imidazole Compounds

The synthesis of 15xaa is outlined in FIG. 12. This route was originallydesigned for the synthesis of 12xa, but the nonselectivity of thebenzoylation at the indole-2 and imidazole-4 positions resulted in theformation of 15xaa, which is a closely related but bulkier analog of11xaa. The indole-5-carboxaldehyde 8x was protected by a phenylsulfonylgroup on the indole NH to afford intermediate 8xa. 8xa was reacted withglyoxal and ammonium hydroxide to generate the 2-aryl-imidazole 9xa.Protection of the imidazole NH with phenylsulfonyl gave the intermediate10xaa which was coupled with 3,4,5-trimethoxybenzoyl chloride to produce16xaa. Removal of the protecting group from 16xaa provided 15xaa.

Synthesis of 1-(Phenylsulfonyl)-1H-indole-5-carbaldehyde (8xa)

To a solution of indole-3-carboxaldehyde (100 mmol) in ethanol (500 mL)at room temperature was added potassium hydroxide (110 equiv), themixture was stirred until total solubilization. The ethanol wascompletely removed in vacuum and acetone (250 mL) added followed bybenzenesulfonyl chloride (110 equiv). The precipitate was filtered offand the filtrate was concentrated and recrystallized from methanol togive a white solid. Yield: 32.6% ¹H NMR (500 MHz, CDCl₃) δ 10.17 (s,1H), 8.25-8.39 (m, 2H), 7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59(t, J=7.5 Hz, 2H), 7.39-7.54 (m, 2H). MS (ESI) calcd for C₁₅H₁₁NO₃S285.1, found 286.0 [M+H]⁺.

Synthesis of(5-(4-(3,4,5-Trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa)

To a solution of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa) (1 mmol) in ethanol (20 mL) was added sodium hydroxide (10equiv) and stirred overnight in darkness. The reaction mixture wasdiluted by 50 mL of water and extracted by ethyl acetate (250 mL). Theorganic layer was dried over magnesium sulfate and concentrated. Theresidue was purified by flash column chromatography (hexane:ethylacetate 3:1) or recrystallized from water and methanol to give a whitesolid. Yield: 30-95%.

5-(1H-Imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9xa)

Yield: 12.0%. ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (d, J=2.9 Hz, 2H), 8.13(d, J=7.8 Hz, 2H), 7.98-8.04 (m, 1H), 7.62-7.67 (m, 1H), 7.55 (d, J=7.82Hz, 2H), 7.22-7.34 (m, 4H). MS (ESI) calcd for C₁₇H₁₃N₃O₂S 323.1, found324.0 [M+H]⁺.

1-(Phenylsulfonyl)-5-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10xaa)

Yield: 23.6%. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=8.5 Hz, 1H), 7.95 (d,J=7.5 Hz, 2H), 7.73 (d, J=1.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 1H), 7.63-7.66(m, 2H), 7.52-7.56 (m, 3H), 7.31-7.34 (m, 3H), 7.22 (t, J=8.5 Hz, 2H),7.17 (s, 1H), 6.14 (d, J=3.5 Hz, 1H). MS (ESI) calcd for C₂₃H₁₇N₃O₄S₂463.1, found 464.0 [M+H]⁺.

(1-(Phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(16xaa)

Yield: 15.9%. ¹H NMR (500 MHz, CDCl₃) δ 8.18-8.25 (m, 3H), 8.04 (d,J=8.1 Hz, 2H), 7.70-7.78 (m, 2H), 7.61-7.69 (m, 3H), 7.55 (t, J=7.7 Hz,3H), 7.50 (s, 1H), 7.38 (s, 2H), 7.34 (s, 2H), 6.94 (s, 1H), 3.99-4.06(m, 12H), 3.94-3.99 (m, 6H). MS (ESI) calcd for C₄₃H₃₇N₃O₁₂S₂ 851.2,found 852.1 [M+H]⁺.

(5-(4-(3,4,5-Trimethoxybenzoyl)-1H-imidazol-2-yl)-1H-indol-2-yl)(3,4,5-trimethoxyphenyl)methanone(15xaa)

Yield: 45.9%; mp 239-241° C. ¹H NMR (500 MHz, CDCl₃) δ 10.45 (s, 1H),9.44 (s, 1H), 8.41 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.61(d, J=8.5 Hz, 1H), 7.29 (s, 2H), 7.26 (s, 2H), 3.99 (s, 3H), 3.95-3.97(m, 15H). MS (ESI) calcd for C₃₁H₂₉N₃O₈ 571.2, found 572.2 [M+H]⁺.HPLC2: t_(R) 4.09 min, purity 96.3%.

Example 7 Synthesis of(Indolyl)-1H-Imidazol-4-yl)(3,4,5-Trimethoxyphenyl)Methanones (17ya),(17yab) and (17yac) (FIG. 13) Synthesis of(2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya)

Synthesis of 1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde (8ya)

To a solution of indole 3-carboxaldehyde (8y) (100 mmol) in ethanol (500mL) at RT was added potassium hydroxide (1.1 equiv). The mixture wasstirred until total solubilization. The ethanol was completely removedin vacuum and the residual was dissolved in acetone (250 mL) followed byadding benzenesulfonyl chloride (1.1 equiv, 110 mmol). The reactionmixture was stirred for half hour. The precipitate was filtered off andthe filtrate was concentrated and recrystallized from methanol to give awhite solid. Yield: 33%. ¹H NMR (500 MHz, CDCl₃) δ 10.17 (s, 1H),8.25-8.39 (m, 2H), 7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59 (t,J=7.5 Hz, 2H), 7.39-7.54 (m, 2H). MS (ESI) calcd for C₁₅H₁₁NO₃S 285.1,found 286.0 [M+H]⁺.

Synthesis of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya)

To a solution of 1-(phenylsulfonyl)-1H-indole-3-carboxaldehyde (8ya)(100 mmol) in ethanol (400 mL) at 0° C. was added a solution of 40%oxalaldehyde (glyoxal) in water (1.1 equiv, 110 mmol) and a solution of29% ammonium hydroxide in water (10 equiv, 1000 mmol). After stiflingfor 2-3 days at RT, the reaction mixture was quenched by water andextracted by dichloromethane. The organic layer was removed by vacuumand the residue was subjected to flash column chromatography withhexane/ethyl acetate (4:1-2:1) as eluent to yield the titled compound asa yellow powder. Yield: 12%. ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (d, J=2.9Hz, 2H), 8.13 (d, J=7.8 Hz, 2H), 7.98-8.04 (m, 1H), 7.62-7.67 (m, 1H),7.55 (d, J=7.82 Hz, 2H), 7.22-7.34 (m, 4H). MS (ESI) calcd forC₁₇H₁₃N₃O₂S 323.1, found 324.0 [M+H]⁺.

Synthesis of1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10ya)

To a solution of 3-(1H-imidazol-2-yl)-1-(phenylsulfonyl)-1H-indole (9ya)(20 mmol) in anhydrous THF (300 mL) at 0° C. was added sodium hydride(60% dispersion in mineral oil, 1.2 equiv, 24 mmol) and stirred for 20min. Benzenesulfonyl chloride (1.2 equiv, 24 mmol) was added and thereaction mixture was stirred overnight. After dilution by 200 mL ofsaturated NaHCO₃ solution (aqueous), the reaction mixture was extractedby ethyl acetate (600 mL). The organic layer was dried over magnesiumsulfate and concentrated. The residue was purified by flash columnchromatography (hexane:ethyl acetate 5:1) to give a white solid. Yield:40%. ¹H NMR (CDCl₃, 300 MHz) δ 8.02-8.08 (m, 4H), 7.72 (d, J=1.5 Hz,1H), 7.35-7.60 (m, 8H), 7.23 (d, J=1.5 Hz, 1H), 7.10-7.16 (m, 3H). MS(ESI) calcd for C₂₃H₁₇N₃O₄S₂ 463.1, found 486.0 [M+Na]⁺.

Synthesis of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yaa)

To a solution of1-(phenylsulfonyl)-3-(1-(phenylsulfonyl)-1H-imidazol-2-yl)-1H-indole(10ya) (5.0 mmol) in anhydrous THF (100 mL) at −78° C. was added 1.7 Mtert-butyllithium in pentane (1.2 equiv, 6.0 mmol) and stirred for 10min. A solution of 3,4,5-trimethoxybenzoyl chloride (1.2 equiv, 6.0mmol) in THF was added at −78° C. and stirred overnight. The reactionmixture was quenched with 100 mL of saturated NaHCO₃ solution (aqueous)and extracted by ethyl acetate (300 mL). The organic layer was driedover magnesium sulfate and concentrated. The residue was purified byflash column chromatography (hexane:ethyl acetate 3:1) to give a whitesolid. Yield: 30%. ¹H NMR (500 MHz, CDCl₃) δ 8.09 (d, J=10 Hz, 1H), 8.04(d, J=10 Hz, 2H), 7.91 (s, 1H), 7.76 (d, J=5 Hz, 2H), 7.65 (t, J=10 Hz,1H), 7.55-7.58 (m, 5H), 7.40 (s, 2H), 7.33-7.36 (m, 3H), 7.25 (t, J=10Hz, 1H), 4.05 (s, 3H), 4.03 (s, 6H). MS (ESI) calcd for C₃₃H₂₇N₃O₈657.0, found 680.1 [M+Na]⁺.

Synthesis of(2-(1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya)

To a solution of(1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yaa) (1 mmol) in ethanol (40 mL) and water (4 mL) was added sodiumhydroxide (10 equiv, 10 mmol) and stirred overnight under refluxingcondition in darkness. The reaction mixture was diluted by 50 mL ofwater and extracted by ethyl acetate (200 mL). The organic layer wasdried over magnesium sulfate and concentrated. The residue was purifiedby flash column chromatography (hexane:ethyl acetate 1:1) to give ayellow solid. Yield: 60%. ¹H NMR (500 MHz, CD₃OD) δ 8.31 (d, J=6.5 Hz,1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48-7.52 (m, 3H), 7.24-7.28 (m, 2H),4.00 (s, 6H), 3.93 (s, 3H). MS (ESI) calcd for C₂₁H₁₉N₃O₄ 377.1, found400.1 [M+Na]⁺. Mp 208-210° C.

Synthesis of(2-(1-(Phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yab)

To a solution of compound 17yaa (66 mg) in THF (1.0 ml) was added 1.0 Mtetrabutyl ammonium fluoride (0.4 mL, 0.4 mmol) and stirred overnight.The reaction mixture was diluted by 20 ml of saturated NaHCO₃ solution(aqueous) and extracted by ethyl acetate (20 ml). The organic layer wasdried over magnesium sulfate and concentrated. The residue was purifiedby flash column chromatography (hexane:ethyl acetate, 2:1) to give apale white solid. Yield: 45%. Mp 110-112° C. ¹H NMR (CDCl₃, 500 MHz) δ8.40-8.42 (m, 2H), 8.09 (d, J=8.0 Hz, 1H), 7.93-7.98 (m, 4H), 7.59 (t,J=7.5 Hz, 1H), 7.41-7.49 (m, 5H), 4.01 (s, 3H), 3.97 (s, 6H). MS (ESI)calcd for C₂₇H₂₃N₃O₆S 517.1, found 540.0 [M+Na]⁺. HPLC: t_(R) 6.81 min,purity 96.3%.

Synthesis of(1-methyl-2-(1-(methyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17yac)

To a solution of 17ya (75 mg, 0.2 mmol) in anhydrous THF (20 ml) at 0°C. was added sodium hydride (60% dispersion in mineral oil, 20 mg, 0.5mmol) and stirred for 20 min. Methyl iodide (70 mg, 0.5 mmol) was added,and the reaction mixture was stirred 1 h. After dilution by 20 ml ofsaturated NaHCO₃ solution (aqueous), the reaction mixture was extractedby ethyl acetate (60 ml). The organic layer was dried over magnesiumsulfate and concentrated. The residue was recrystallized from water andmethanol to give a white solid. 75% yield. Mp 164-166° C. ¹H NMR (CDCl₃,500 MHz) δ 8.30 (d, J=7.5 Hz, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.41 (t,J=8.5 Hz, 1H), 7.39 (s, 1H), 7.35 (t, J=7.0 Hz, 1H), 7.23 (t, J=7.0 Hz,1H), 3.98 (s, 6H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H). MS (ESI)calcd for C₂₃H₂₃N₃O₄ 405.2, found 406.4 [M−+H]⁺. HPLC: t_(R) 4.80 min,purity>99%.

Example 8 Synthesis of(2-(1H-Indol-5-Ylamino)Thiazol-4-yl)(3,4,5-Trimethoxyphenyl)Methanone(Compound 55) (FIG. 15)

A mixture of 5-nitro-1H-indole (11 g, 67.9 mmol) and Pd/C (5%; 1g),dissolved in ethanol (50 mL), was hydrogenated for 3 h at 40 psi. Thereaction mixture was filtered and the excess of ethanol was evaporatedunder reduced pressure. Solid product was recrystallized from hexane toobtain the pure compound 5-aminoindole (55-1). Yield: 92.5%. ¹H NMR (500MHz, CDCl₃): δ 7.96 (br, 1H), 7.20 (d, 1H), 7.13 (s, 1H), 6.95 (s, 1H),6.67 (dd, 1H), 6.37 (s, 1H), 3.50 (s, 2H). MS (ESI) m/z 133.0 (M+H)⁺

A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) wasreacted with benzoylisothiocyanate (9.88 g, 60. mmol) at RT for about 4h. The resulting solid was filtered and treated with 2 N NaOH in THF(120 mL). The mixture was refluxed for about 6 h and allowed to warm toRT. The solvent was evaporated off under vacuum. The residue was dilutedwith water (20 mL) and neutralized to pH 7 with 1 N HCl. The resultingsolid was filtered and dried under vacuum to afford 5-indolylthiourea(55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. Thereaction was cooled, the crystalline ethyl2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected byfiltration and washed with ethanol. Refluxing the mixture of ethylesters with the NaOH-ethanol solution gave2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was useddirectly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI(2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH₂Cl₂ (30 mL) wasadded HNCH₃OCH₃HCl salt (2.6 mmol) and stirring continued at RT forovernight. The reaction mixture was diluted with CH₂Cl₂ (20 mL) andsequentially washed with water, satd. NaHCO₃, brine and dried overMgSO₄. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography to obtain purecompound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide(55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF wascharged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar₂ protectionand stirred for 10 min Weinreb amide (1 mmol) in 10 mL THF was added tolithium reagent and allowed to stir at RT for 2 h. The reaction mixturewas quenched with satd. NH₄Cl, extracted with ethyl ether, dried withMgSO₄. The solvent was removed under reduced pressure to yield a crudeproduct, which was purified by column chromatography to obtain purecompound 55 (51.7% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.29 (br, 1H), 7.68(d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28-7.26 (m, 1H),7.15-7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI)m/z 432.1 (M+Na)⁺, 408.0 (M−H)⁻.

Example 9 Synthesis of Quinoline- and Isoquinoline-Aryl Compounds (FIG.16)

A series of compounds were prepared by Suzuki coupling of7-bromo-1-chloroisoquinoline with various arylboronic acids.

Synthesis of 1-Chloro-7-(1H-indol-5-yl)-isoquinoline (6d) (FIG. 16C)

A mixture of 7-bromo-1-chloroisoquinoline (0.50 g, 2.1 mmol),5-indoleboronic acid (0.40 g, 2.5 mmol),tetrakis(triphenylphosphene)palladium (0.035 g, 0.08 mmol), potassiumcarbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) wasstirred while purging the headspace with argon for 30 min. The mixturewas then brought to reflux for 16 h before being allowed to cool to RT.The mixture was filtered through a bed of silica gel, diluted with water(50 mL), and extracted with ethyl acetate (50 mL). The organic layer wasseparated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, untilrefractive changes were no longer seen at the organic-aqueousinterface), and ammonium chloride (20 mL, sat.). The organic layer wasthen adsorbed onto silica gel and flash-chromatographed (ethylacetate/hexanes) to afford 0.14 g (25%) of a yellow solid. MS (ESI):calculated for C₁₇H₁₁ClN₂, 278.1, found 301.0 [M+Na]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 6.56-6.58 (m, 1H), 7.44 (t, J=2.77 Hz, 1H), 7.57-7.59 (m,2H), 7.93 (m, 1H), 8.04 (s, 1H), 8.13-8.20 (m, 1H), 8.27-8.31 (m, 2H),8.43 (m, 1H), 11.25 (brs, 1H).

1,7-Bis-(1H-indol-5-yl)-isoquinoline (6b) (FIG. 16E)

A mixture of 7-bromo-1-chloroisoquinoline (0.20 g, 2.1 mmol),5-indoleboronic acid (0.80 g, 5.0 mmol),tetrakis(triphenylphosphene)palladium (0.19 g, 0.16 mmol), potassiumcarbonate (2.1 mL, 2 M, 4.1 mmol), N,N-dimethylformamide (11 mL) wasstirred while purging the headspace with argon for 30 min. The mixturewas then brought to reflux for 16 h before being allowed to cool to RT.The mixture was filtered through a bed of silica gel, diluted with water(50 mL), and extracted with ethyl acetate (50 mL). The organic layer wasseparated and washed with NaOH (2×20 mL, 10% aq.), water (5×30 mL, untilrefractive changes were no longer seen at the organic-aqueousinterface), and ammonium chloride (20 mL, sat.). The organic layer wasthen adsorbed onto silica gel and flash-chromatographed (ethylacetate/hexanes) to afford 0.29 g (39%) of a yellow solid. MS (ESI):calculated for C₂₅H₁₇N₃, 359.1, found 360.2 [M+H]+382.1 [M+Na]⁺, and358.0 [M−H]⁻. ¹H NMR (500 MHz, DMSO-d₆) δ 6.46-6.50 (m, 1H) 6.52-6.59(m, 1H) 7.34-7.36 (m, 1H) 7.36-7.41 (m, 2H) 7.42-7.52 (m, 3H) 7.58 (d,J=8.30 Hz, 1H) 7.81 (dd, J=5.49, 5.00 Hz, 2H) 7.92 (s, 1H) 8.08-8.17 (m,2H) 8.33 (s, 1H) 8.54 (d, J=5.61 Hz, 1H) 11.18 (br. s., 1H) 11.30 (br.s., 1H) ppm.

1-(4-Fluoro-phenyl)-7-(1H-indol-5-yl)-isoquinoline (6c) (FIG. 16D)

A mixture of 6d (0.20 g, 0.72 mmol), 4-fluorophenylboronic acid (0.12 g,0.86 mmol), tetrakis(triphenylphosphene)palladium (0.033 g, 0.03 mmol),potassium carbonate (0.72 mL, 2 M, 1.4 mmol), N,N-dimethylformamide (22mL) was stirred while purging the headspace with argon for 30 min. Themixture was then brought to reflux for 16 h before being allowed to coolto RT. The mixture was filtered through a bed of silica gel, dilutedwith water (50 mL), and extracted with ethyl acetate (50 mL). Theorganic layer was separated and washed with NaOH (2×20 mL, 10% aq.),water (5×30 mL, until refractive changes were no longer seen at theorganic-aqueous interface), and ammonium chloride (20 mL, sat.). Theorganic layer was then adsorbed onto silica gel andflash-chromatographed (ethyl acetate/hexanes) to afford 0.038 g (16%) ofa yellow solid. MS (ESI): calculated for C₂₃H₁₅FN₂, 338.12, found 339.2[M+H]⁺ and 361.2 [M+Na]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 6.47-6.55 (m, 1H),6.80 (d, J=9.16 Hz, 2H), 7.38-7.45 (m, 2H), 7.47-7.62 (m, 3H), 7.72 (d,J=8.85 Hz, 2H), 7.79-7.96 (m, 3H), 11.18 (br. s., 1H).

1,7-Bis-(4-fluoro-phenyl)-isoquinoline (40) (FIG. 16A)

MS (ESI): calculated for C₂₁H₁₃F₂N, 317.10, found 318.1 [M+H]⁺, 340.1[M+Na]⁺, and 315.9 [M−H]⁻. ¹H NMR (500 MHz, DMSO-d₆) δ 7.31 (br. s., 1H)7.31-7.37 (m, 2H) 7.39 (br. s., 1H) 7.41 (t, J=8.54 Hz, 2H) 7.72-7.77(m, 2H) 7.78-7.84 (m, 2H) 7.89 (br. s., 1H) 7.90-7.99 (m, 1H) 8.09-8.19(m, 3H) 8.59 (br. s., 1H) 8.60-8.65 (m, 1H).

Synthesis of7-Bromo-1-(4-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline (43)and1-(4-Fluoro-benzenesulfonyl)-7-(1H-indol-5-yl)-1,2,3,4-tetrahydroquinoline(41). (FIG. 16B)

7-Bromo-1,2,3,4-tetrahydroquinoline (0.60 g, 2.8 mmol) was stirred with4-fluorophenylsulphonyl chloride (1.65 g, 8.49 mmol) in pyridine (5 mL)at 80° C. for 3 h. The mixture was cooled, concentrated, and the residuewas chromatographed (EtOAc/Hexanes on SiO₂) to give 845 mg of a brownsolid (81%) of compound 43. C₁₅H₁₃BrFNO₂S 368.98, found 394.0 [M+Na]⁺and 367.8 [M−H]⁻. ¹H NMR (500 MHz, CDCl₃) δ 1.58-1.67 (m, 2H) 2.41 (t,J=6.71 Hz, 2H) 3.72-3.82 (m, 2H) 6.89 (d, J=8.30 Hz, 1H) 7.08-7.17 (m,2H) 7.18-7.24 (m, 1H) 7.59-7.68 (m, 2H) 7.92-8.01 (m, 1H).

43 (0.46 g, 1.3 mmol), 5-indoleboronic acid (0.26 g, 1.6 mmol),tetrakis(triphenylphosphene)palladium (0.031 g, 0.03 mmol), potassiumcarbonate (1.35 mL, 2-M, 2.7 mmol), and N,N-dimethylformamide (135 mL)were stirred while purging the headspace with argon for 30 min. Themixture was then brought to reflux for 16 h before being allowed to coolto RT. The mixture was filtered through a bed of silica gel, dilutedwith water (50 mL), and extracted with ethyl acetate (50 mL). Theorganic layer was separated and washed with NaOH (2×20 mL, 10% aq.),water (5×30 mL, until refractive changes were no longer seen at theorganic-aqueous interface), and ammonium chloride (20 mL, sat.). Theorganic layer was then adsorbed onto silica gel andflash-chromatographed (ethyl acetate/hexanes) to afford 0.38 g (77%) ofa white crystalline solid of compound 41. MS (ESI): calculated forC₂₃H₁₉FN₂O₂S, 406.12, found 404.9 [M−H]⁻ and 429.1 [M+Na]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 1.56-1.66 (m, 2H) 2.48 (t, J=6.59 Hz, 2H) 3.76-3.86 (m,2H) 6.46-6.56 (m, 1H) 7.14 (m, J=7.81 Hz, 1H) 7.33-7.37 (m, 1H)7.38-7.45 (m, 4H) 7.49 (m, J=8.54 Hz, 1H) 7.66-7.74 (m, 2H) 7.74-7.81(m, 1H) 7.85-7.94 (m, 1H) 11.17 (br. s., 1H).

7-Bromo-2-(4-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoline(42) (FIG. 16B)

Yield 23%. C₁₅H₁₃BrFNO₂S, 369.0, found 392.0 [M+Na]⁺ and 367.7 [M−H]⁻.¹H NMR (500 MHz, DMSO-d₆) δ 2.75-2.82 (m, 2H) 3.32 (t, J=6.10 Hz, 2H)4.24 (s, 2H) 7.07 (d, J=8.30 Hz, 1H) 7.29-7.37 (m, 1H) 7.37-7.43 (m, 1H)7.47 (t, J=8.79 Hz, 2H) 7.87-7.93 (m, 2H).

2-(4-Fluoro-benzenesulfonyl)-7-(1H-indol-5-yl)-1,2,3,4-tetrahydro-isoquinoline(44)

Yield 77%. ¹H NMR (500 MHz, DMSO-d₆) δ 2.84-2.91 (m, 2H) 3.35 (t, J=5.98Hz, 2H) 4.30 (s, 2H) 6.44-6.48 (m, 1H) 7.17 (d, J=7.81 Hz, 1H) 7.32-7.40(m, 2H) 7.41-7.51 (m, 3H) 7.75-7.79 (m, 1H) 7.89-7.96 (m, 1H) 11.13 (br.s., 1H).

Example 10 Water Solubility of Aryl-Benzoyl-Imidazole (ABI) Compounds(FIG. 17)

Determination of Water Solubility.

To determine water solubility, 1 mg of each compound was suspended in 1mL water and shaken for 48 h at room temperature (RT). The suspensionwas centrifuged at 10,000 rpm for 10 min and filtered on 0.22 μm filter.

Concentrations of each compound were measured by LC-MS, consisting of anHP S1100 HPLC instrument (Agilent, Foster ceity, CA) and a BrukerESQUIRE MS detector with electrospray/ion trap instrument in positiveion mode (Bruker, Fremont, Calif.). For HPLC, a reverse phase Nova-pakC18 column (150 mm×3.9 mm, Waters, Milford, Mass.) was used. The mobilephase was composed of 20:80 v/v water/acetonitrile. For MASS, the peakwas extracted at 382 m/z (for imidazole compounds) and 399 m/z (forthiazole compounds) respectively. The concentration of each compound wascalculated by MS peak area according to the following calibrationequation: y=1.3295x+114.24 (R²=1.00). To make the standard curve (FIG.17) from which the equation was derived, 50, 100 μL, of each 100 μg/mL,10 μg/mL of ABI compound 12ga, and its corresponding thiazole analog, aswell as CA-4 (see FIG. 19 for structure) in acetonitrile, were injectedinto HPLC and monitored by mass spectroscopy. The amount (ng) in eachinjection was plotted again its relative mass peak area to generate thestandard curve in FIG. 17.

The HPLC retention times of ABI compound 12ga (1.5 min) was compared toits corresponding thiazole analog (2.2 min) using 80/20 methanol/watermobile phase at 1 mL/min flow rate and a reversed phase column,indicating that the imidazole derivative was more hydrophilic than itscorresponding thiazole analog. The calculated logP values for ABIcompound 12ga and the corresponding thiazole analog were approximately2.9 and 4.4, respectively. The water solubility of compound 12ga was 13μg/mL, or about 200 times greater than its thiazole counterpart (72ng/mL).

Example 11 Biological Evaluation of Compounds of this Invention Example11A In Vitro Cell Growth Inhibitions

Cell Culture and Cytotoxicity Assay of Prostate Cancer and Melanoma. Allcell lines were obtained from ATCC (American Type Culture Collection,Manassas, Va., USA), while cell culture supplies were purchased fromCellgro Mediatech (Herndon, Va., USA). We examined the antiproliferativeactivity of our anti-tubulin compounds in four human prostate cancercell lines (LNCaP, DU 145, PC-3, and PPC-1) and two human melanoma celllines (A375 and WM-164). Human ovarian cell line OVCAR-8 and itsresistant cell line that over-expresses P-gp (NCI/ADR-RES) were used asMDR models. Both ovarian cell lines were obtained from National CancerInstitutes (NCI). All cell lines were tested and authenticated by eitherATCC or NCI. All prostate cancer and ovarian cancer cell lines werecultured in RPMI 1640, supplemented with 10% fetal bovine serum (FBS).

Melanoma cells were cultured in DMEM, supplemented with 5% FBS, 1%antibiotic/antimycotic mixture (Sigma-Aldrich, Inc., St. Louis, Mo.,USA) and bovine insulin (5 μg/mL; Sigma-Aldrich). The cytotoxicpotential of the anti-tubulin compounds was evaluated using thesulforhodamine B (SRB) assay after 96 h of treatment.

All of the reported compounds were first evaluated for cytotoxicity inthe mouse melanoma cell line B16-F1, human melanoma cell lines (A375 andWM-164) and prostate cancer cell lines (DU145, PC-3, LNCaP, PPC-1).Compound 1h and ABT-751 (E7010, Abbott Laboratories/Eisai Co Ltd), whichhas entered phase II clinical studies in treating patients withdifferent cancers, were included in the assays as examples ofcolchicine-site binding agents. IC₅₀ values for cell growth inhibitionare shown in Tables 1, 2 and 3.

Results:

TABLE 1 SAR of B ring Optimizing Compounds

IC₅₀ ± SEM (nM) B ring B16-F1 A375 DU 145 PC-3 LNCaP PPC-1 1a 1,3-phenyl500 ± 200 87 ± 15  178  81  234  85 1b 4,6-pyrimidine >30000 >30000 69008300 7000 3700 1c 2,6-pyridine 39 ± 12 30 ± 14 33 ± 3  32 ± 2  27 ± 2 25 ± 1  1d 2,5-furan 151 ± 24  27 ± 8   35  21  23  20 1e 2,5-thiazole12500 ± 5200  13600 ± 3800 >10000  >10000  >10000  >10000  1f2,4-thiophene 72 ± 15 15 ± 6   26  12  17  15 1g1,4-piperidine >30000 >30000 >20000  >20000  >20000  >20000  1h2,4-thiazole 55 ± 5  28 ± 5  71 ± 4  21 ± 1  28 ± 4  43 ± 5  1i3,5-isoxazole >30000 >30000 >10000  >10000  >10000  >10000  36a 2,4-oxazole 600 ± 200 300 ± 100  292  294  310  324 35a  2,4-oxazoline6500 ± 800  500 ± 100 1200 ± 100  1200 ± 100  1200 ± 100  1100 ± 100 

TABLE 2 SAR of Carbonyl Linker Optimizing Compounds IC₅₀ ± SEM (nM)

                    X linker                     B16-F1                    A375                     WM-164                     DU 145                    PC-3                     LNCaP                     PPC-1 1hC═O 55 ± 5  28 ± 5  64 ± 4  71 ± 4  21 ± 1  28 ± 4  43 ± 5  2a C═CMe₂3800 ± 1300 1900 ± 800  3700 ± 1200  2650  2470  1390  2040 2bCHOH >30000 >30000 ND  >10000 >10000 >10000 >10000 2c-trans syn-C═C—CN5400 ± 2100 4600 ± 1500 4900 ± 1300  2280   890   580   900 2c-cis anti-C═C—CN 1200 ± 300  1200 ± 400  1000 ± 200  ~10000 ~10000  1990 ~100002d-cis syn- C═N—NH₂ 2000 ± 800  900 ± 300 ND   1210  1120  1800   8722d-trans Anti- C═N—NH₂ 1800 ± 700  600 ± 200 ND   1210  1040  1300   9662e-cis syn- C═N—OH 300 ± 100 200 ± 100 ND*   102   120   189   1602e-trans anti- C═N—OH 11400 ± 2100  7800 ± 1200ND  >10000 >10000 >10000 >10000 2f-cis syn- C═N—OMe 3800 ± 1600 2900 ±1200 3400 ± 1800 >10000 >10000 >10000 >10000 2f-transAnti-C═N—OMe >10000 >10000 >10000 >10000 >10000 >10000 >10000 2gCONH >30000 >30000 ND  >10000 >10000 >10000 >10000 2h NHCO >30000 >30000ND  >10000 >10000 >10000 >10000 2i Bond(none) >10000 >10000 >10000 >10000 >10000 >10000 >10000 2j C═N—CN 60 ±21 28 ± 12 27 ± 13 42 ± 2  27 ± 1  23 ± 2  20 ± 1  3a cis-C═C 11000 ±2800  46500 ± 23300 10600 ± 5800  >10000 >10000 >10000 >10000 3btrans-C═C 32800 ± 13000 >10000 30800 ± 12000 >10000 >10000 >10000 >100004a S 2400 ± 900  1600 ± 400  2000 ± 1200 >10000 >10000 2300 ± 200  2300± 100  4b SO₂ >10000 >10000 >10000 >10000 >10000 >10000 >10000 4cSO >10000 >10000 >10000 >10000 >10000 >10000 >10000 4dSO₂NH₂ >10000 >10000 >10000 >10000 >10000 >10000 >10000 *ND = Notdetermined

TABLE 3 Antiproliferative Activity of Modified Compounds with ImprovedAqueous Solubility IC₅₀ ± SEM (nM)

                        A part                         B16-F1                        A375                         DU 145                        PC-3                         LNCaP                         PPC-1 58a4-OTBDMSPh 500 ± 200 700 ± 300 434 ± 30  183 ± 24   549 246 ± 8  214-OHPh   110   100   116   87  103   76 62a 2-indolyl 43 ± 21 19 ± 9   32   24  28   28 66a 5-indolyl 25 ± 13 8 ± 1   13    7  10    8 68a4-BocNHCH₂Ph 2900 ± 400  7900 ± 500   4400  3100 2600  2700 2r4-NH₂CH₂Ph 38 ± 11 41 ± 13   25   80  13   34 2s4-NHMeCH₂Ph >10000 >10000 ~10000 >10000 114 ± 80   ~1000 2u4-NMe₂CH₂Ph >10000 >10000 >10000 >10000 1025 ± 200  >10000 5a PhNH 65 ±12 45 ± 8 70 ± 4  57 ± 3  51 ± 1  54 ± 1  5Hb 4-CH₃PhNH ND* ND 35 ± 1 38 ± 2  35 ± 1  36 ± 1  5c 4-FPhNH ND  ND 63 ± 1  43 ± 1  41 ± 1  37 ±1  1h Ph 55 ± 5  28 ± 5  71 ± 4  21 ± 1  28 ± 4  43 ± 5  ABT-751 2127 ±351  1111 ± 108  839 ± 719  786 ± 89  658 ± 117 701 ± 307 *ND = Notdetermined

SAR of Alternative “B” Ring Molecules.

The first series was targeted to alternatives to the thiazole “B” ring.Accordingly, a series of heterocyclic “B” rings were examined. As shownin Table 1, the successful replacements of the thiazole were pyridine1c, furan 1d and thiophene 1f. The IC₅₀s (12 nM˜35 nM against prostatecancer cells) are close to the thiazole compound 1h. Introducing phenyl(1a), oxazoline (35a), and oxazole (36a) maintained activity in thehundreds of nanomolar range. But introducing of pyrimidine (1b, IC₅₀:3.7˜8.3 μM), a reversed 2,5-thiazole and 3,5-isoxazole (1e and 1i,IC₅₀: >10 μM) caused obvious losses of potency. Modification of “B” ringto the saturated ring of piperidine (1g) also totally abolished activity(IC₅₀>20 μM).

SAR of Alternative Linkers.

In vitro hepatic metabolic stability studies revealed that the carbonyllinker between “B” and “C” rings in SMART compounds caused short halflives (5-17 min) primarily due to carbonyl reduction. For the sake ofblocking this ketone reduction to the inactive hydroxyl linker compound2b, the carbonyl linker in the second series of compounds was modified(Table 2). The carbonyl linker was replaced with double bonds (2a, 3aand 3b), amides (2g, 2h), oximes (2e-cis,trans and 2f-cis,trans),hydrazide (2d-cis, 2d-trans), acrylonitriles (2c-trans, 2c-cis),cyanoimine (2j), sulfonyl amide (4d), sulfur ether (4a), sulfonyl andsulfinyl compounds (4b, 4c). A direct link compound 2i without anylinker between “B” and “C” rings was also prepared. Among these linkermodifications, only cyanoimine linkage (2j) showed promising potential(20˜60 nM) compared with carbonyl compound 1h, but an in vitrometabolism study showed that the half life of 2j in human livermicrosome was less than 5 min. This suggested that although the ketonereduction is blocked, it might introduce a new metabolic liability incompound 2j. The isomer pairs of compounds containing double bonds,oximes and hydrazides were separated. Compound 3a was designed to mimicthe structure of CA-4, (FIG. 19) which contain a cis-C═C between twoaryl rings, unfortunately 3a and other isomer pairs lost activity afterreplacing the C═O linker. One interesting phenomenon is syn-isomer of2e-cis (0.1˜0.3 μM) showed 10 fold more activity than its anti-isomer2e-trans (>10 μM). The half life of 2e-cis in human liver microsome isextended to 35 min, while half lives of compounds 2d can be prolonged to55 min. But decreased activity (˜1 μM) of 2d also reduced their potency.

Example 11B Aqueous Solubility of Compounds of the Invention

The solubility of drugs was determined by Multiscreen Solubility FilterPlate (Millipore Corporate, Billerica, Mass.) coupled with LC-MS/MS.Briefly, 198 μL of phosphate buffered saline (PBS) buffer (pH 7.4) wasloaded into 96-well plate, and 2 μL of 10 mM test compounds (in DMSO)was dispensed and mixed with gentle shaking (200-300 rpm) for 1.5 h atRT (N=3). The plate was centrifuged at 800 g for 5 min, and the filtratewas used to determine its concentration and solubility of test compoundby LC-MS/MS as described below.

Introducing Polar and Ionizable Groups into the Anti-Tubulin Agents.

One major limitation of the SMART agents is low aqueous solubility.Surfactants such as Tween 80, were used to study in vivo SMART behavior,accordingly favorable results were obtained. But these surfactants arebiologically active and are responsible for many side effects. Inaddition, it was thought that low aqueous solubility of 1h resulted inlow oral bioavailability (3.3%, Table 4). In the third series ofcompounds, the aqueous solubility was successfully increased withoutimpacting the potency by introducing polar groups like hydroxyl andindolyls. In addition, ionizable groups like amino and alkylamino groupswere also introduced into “A” ring para-position. As shown in FIG. 5 andTable 3, introducing indolyl groups to the “A” ring especially 5-indolyl(66a, 7˜25 nM) increased the potency compared with the 4-OH compound 2l(76-116 nM). Aminomethyl —CH₂NH₂ at the “A” ring para position alsomaintained potency (2r, 13-80 nM), but p-NHMe (2s) or p-NMe₂ (2u)abrogated activity. As shown in FIG. 18, analytical measurement toestimate aqueous solubility showed that indolyl compound 66a increasedsolubility in PBS from 1.1 μg/mL (compound 1h) to 3.8 μg/mL. Aminomethylcompound 2r was converted to the HCl salt, which increased solubilityover 35-fold (>35 μg/mL). Although compound 2r showed satisfactoryaqueous solubility, the pharmacokinetic studies showed this compoundstill had very poor bioavailability (F %=0.2%). It was thought thatcompound 2r was ionized in the stomach, and therefore not absorbed intothe circulation system.

Example 11C Pharmacokinetic Studies

Pharmacokinetic Study.

Female Sprague-Dawley rats (n=3 or 4; 254±4 g) were purchased fromHarlan Inc. (Indianapolis, Ind.). Rat thoracic jugular vein catheterswere purchased from Braintree Scientific Inc. (Braintree, Mass.). Onarrival at the animal facility, the animals were acclimated for 3 daysin a temperature-controlled room (20-22° C.) with a 12 h light/darkcycle before any treatment. Compound 1h was administered intravenously(i.v.) into the jugular vein catheters at a dose of 2.5 mg/kg (inDMSO/PEG300, 2/8), whereas 5Ha and 5Hc were dosed at 5 mg/kg (inDMSO/PEG300, 1/9). An equal volume of heparinized saline was injected toreplace the removed blood, and blood samples (250 μL) were collected viathe jugular vein catheters at 10, 20, 30 min, and 1, 2, 4, 8, 12, 24 h.Compounds 1h, 5Ha and 5Hc were given (p.o.) by oral gavage at 10 mg/kg(in Tween80/DMSO/H₂O, 2/1/7). All blood samples (250 μL) after oraladministration were collected via the jugular vein catheters at 30, 60,90 min, 120 min, 150 min, 180 min, 210 min, 240 min, and 8, 12, 24 h.Heparinized syringes and vials were prepared prior to blood collection.Plasma samples were prepared by centrifuging the blood samples at 8,000g for 5 min. All plasma samples were stored immediately at −80° C. untilanalyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard((3,5-dimethoxyphenyl)(2-phenyl-1H-imidazol-4-yl)methanone). The sampleswere thoroughly mixed, centrifuged, and the organic extract wastransferred to autosampler for LC-MS/MS analysis. Multiple reactionmonitoring (MRM) mode, scanning m/z 356→188 (compound 1h), m/z 371→203(compound 5Ha), m/z 389→221 (compound 5Hc), and m/z 309→171 (theinternal standard), was used to obtain the most sensitive signals. Thepharmacokinetic parameters were determined using non-compartmentalanalysis (WinNonlin, Pharsight Corporation, Mountain View, Calif.)

Results:

TABLE 4 Pharmacokinetic Parameters for Compounds Tested in vivo. 1h 2r5Ha 5Hc Route IV PO IV PO IV PO IV PO N^(a) 4   3 3   3 3 3 3 3 Dose(mg/kg) 2.5 10 2.5 4 5 10  5 10  CL^(b) (mL/min/kg) 7.7 ± 1.0 — 22 ± 13— 17 ± 3 — 13 ± 2 — Vss^(c) (L/kg) 4.9 ± 1.9 — 0.33 ± 0.25 —  1.4 ± 0.2—  1.4 ± 0.2 — AUC^(d) (min * mg/mL) 279 ± 53  37 ± 20 139 ± 77    0.4296 ± 46 65 ± 20 381 ± 65 160 ± 13 C_(max) ^(e) (ng/mL) 3816 ± 509  2123.2 ± 1.6 3794 ± 1580 4198 ± 438 814 ± 255 3349 ± 686 1262 ± 362 F^(f)(%) 3.3 0.2 11  21  ^(a)Numbers of rats. ^(b)Systemic clearance.^(c)Volume of distribution following intravenous dosing. ^(d)Area underthe curve following intravenous dosing, integrated drug concentrationwith respect to time and integrated drug concentration with respect totime following oral dosing. ^(e)Maximum plasma concentration followingintravenous dosing. ^(f)Percent oral bioavailability.

Modifying Substituted Methoxybenzoyl Aryl Thiazole (SMART) Molecules toImprove Oral Bioavailability.

Many established tubulin targeting anticancer drugs like taxanes andvinblastine require intravenous administration because of low oralbioavailability. Oral bioavailability is a complex parameter involvingmany chemical and physiological processes, such as solubility,permeability, and metabolic stability. The solubility of these tubulininhibitors was improved by inserting an amino linker between the “A” and“B” rings as in 5a-d (FIG. 6), Table 3 demonstrates that the NH bridgedcompounds (5a-c) had similar potency (35˜65 nM) as 1h with increasedsolubility (15 and 19 μg/mL for 5a and 5c, respectively (FIG. 18), butthey are over 20 fold more active than ABT-751 (Table 3 and FIG. 19 forthe structure of ABT-751).

Rat pharmacokinetic studies were performed to study whether these newcompounds exhibited improved bioavailability compared to compound 1h(Table 4). The data clearly showed that 5Hc (HCl salt of 5c) exhibitedmore than 4.3-fold increased exposure (AUC) by the oral route ascompared to 1h, suggesting that improved aqueous solubility by the aminolinker successfully improved oral bioavailability. In addition, themaximal concentration (Cmax) of 5Ha and 5Hc by oral administration was814 and 1262 ng/mL, respectively. While Cmax of 1h was only 212 ng/mL.Overall, the bioavailability of 5Ha and 5Hc was increased from 3.3% of1h to 11% and 21%, respectively (Table 4). Compound 5Hc exhibitedmoderate clearance, moderate volume of distribution, and acceptable oralbioavailability. This data suggested that these new synthesized aminolinked compounds have the potency and PK profile to be developed as anew class of orally bioavailable antitubulin agents.

Example 11D In Vitro Tubulin Polymerization Inhibition by Compounds ofthe Invention

In Vitro Tubulin Polymerization Assay.

Bovine brain tubulin (0.4 mg, >97% pure) (Cytoskeleton, Denver, Colo.)was mixed with 10 μM of the test compounds and incubated in 100 μl ofgeneral tubulin buffer (80 mM PIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, and 1 mMGTP) at pH 6.9. The absorbance of wavelength at 340 nm was monitoredevery 1 min for 20 min by the SYNERGY 4 Microplate Reader (Bio-TekInstruments, Winooski, Vt.). The spectrophotometer was set at 37° C. fortubulin polymerization.

Results:

The inhibition of tubulin polymerization by selected potent compounds1c, 2j, 66a, and 5a was investigated by all three design strategies(alternative B-rings, novel linkers, and solubilizing moieties) andcompared with 1h. Bovine brain tubulin (>97% pure) was incubated withthe individual compounds (10 μM) to test their effect on tubulinpolymerization (FIG. 20 a). After 20 min incubation, tubulinpolymerization was inhibited 47% by 1h, as compared to vehicle. Both 1cand 2j inhibited 64% of polymerization at 20 min with differentinhibition patterns. Compounds 5a and 66a provided greater inhibitionsas 78% and 81%, respectively. These data suggest that these compoundsexhibit strong antitubulin polymerization activity that corresponds wellwith their cytotoxicity.

The inhibition of tubulin polymerization by compound 5c by binding withcolchicines binding site and compared with compound 1h is demonstratedin FIGS. 20 b and 20 c.

Example 11E Novel Anti-Tubulin Compounds Overcome P-GlycoproteinMediated Multidrug Resistance

The P-glycoprotein (P-gp) system appears to be a primary physiologicalmechanism of multidrug resistance (MDR) which acts as an ATP-dependentdrug efflux pump, actively removing a variety of structurally diversecytotoxic compounds. Enhanced efflux of these compounds reduces theirintracellular accumulation and so reduces their cytotoxicity. Therefore,novel compounds which are not susceptible to drug resistance could be ofhigh therapeutic and economic value. In addition to P-gp, clinicallyused antitubulin agents have other resistance mechanisms such as changesin microtubule dynamics and mutations in β-tubulin which are known tolimit sensitivity to the taxanes. The anti-tubulin compounds of theinvention were tested against an ovarian cancer cell line OVCAR-8(parent) and P-gp over-expressing NCI/ADR-RES cell line (Tables 5A, 5B).

Results:

TABLE 5A Antiproliferative Activity of Selected Compounds against P-gpover-expressed MDR cell lines. IC₅₀ (nM) Resistance Compound OVCAR-8NCI/ADR-RES factor 1c 33 ± 3   13 ± 0.8 0.4 2j 34 ± 2 14 ± 1 0.4 66a 10± 3  4 ± 2 0.4 2r 26 ± 2 11 ± 2 0.4 5a 46 ± 6 27 0.6 5b 28 21 0.8 5c 44± 3 25 ± 6 0.6 1h 35 ± 2 13 ± 1 0.4 paclitaxel*  4.7 ± 0.1 6263 ± 6341333 vinblastine  3.9 ± 0.1 582 ± 57 149 colchicine 17 ± 1 1113 ± 79  65

Notably, the anti-tubulin compounds of the invention demonstratedequipotent antiproliferative effects against OVCAR-8 and NCI/ADR-REScell lines, suggesting that they are not P-gp substrates and that theyfunction in a P-gp-independent manner. This feature is distinct fromthat of paclitaxel, vinblastine, and colchicine in NCI/ADR-RES cells.

TABLE 5B Antiproliferative activity of selected phenyl-amino thiazolecompounds IC₅₀ ± SEM (nM) R B16-F1 A375 DU 145 PC-3 LNCaP PPC-1 5a H  65± 12 45 ± 8 70 ± 4 57 ± 3 51 ± 1 54 ± 1 5Hb 4-CH₃ ND* ND 35 ± 1 38 ± 235 ± 1 36 ± 1 5c 4-F ND ND 63 ± 1 43 ± 1 41 ± 1 37 ± 1 5d 4-Cl ND 25 ± 773 ± 1 33 ± 1 45 ± 1 36 ± 1 1h — 55 ± 5 28 ± 5 71 ± 4 21 ± 1 28 ± 4 43 ±5 ABT-751 — 2127 ± 351 1111 ± 108  839 ± 719 786 ± 89  658 ± 117  701 ±307

The phenyl amino thiazole compounds 5a, 5Hb, 5c and 5d demonstratedpotent activity in a number of prostate cancer cell lines. Unexpectedly,the phenyl amino imidazole compound 5e demonstrated no activity(IC₅₀>1000 nM in LNCaP, PC-3, DU-145, and PPC-1) in these prostatecancer cell lines. The positive controls for this experiment were 55 and17ya which demonstrated IC₅₀ values between 7.5 nM and 24.1 nM in thesame cell lines (Table 5C).

TABLE 5C Table 5C. IC₅₀ ± SEM (nM) B16-F1 A375 DU 145 PC-3 LNCaP PPC-15a  65 ± 12 45 ± 8 70 ± 4 57 ± 3 51 ± 1 54 ± 1 5Hb ND ND 35 ± 1 38 ± 235 ± 1 36 ± 1 5c ND ND 63 ± 1 43 ± 1 41 ± 1 37 ± 1 5d ND 25 ± 7 73 ± 133 ± 1 45 ± 1 36 ± 1 1h 55 ± 5 28 ± 5 71 ± 4 21 ± 1 28 ± 4 43 ± 5ABT-751 2127 ± 1111 ± 839 ± 786 ± 89 658 ± 701 ± 351 108 719 117 307 dND ND >1000 >1000 >1000 >1000 e ND ND >1000 >1000 >1000 >1000 5e NDND >1000 >1000 >1000 >1000 55 ND ND 24 ± 6 12 ± 1 13 ± 1 15 ± 1 17ya NDND 11 ± 1  5 ± 2  8 ± 2  8 ± 1

A new series of tubulin polymerization inhibitors with acceptable oralbioavailability and equi-potent activity in multidrug resistant tumorcell lines has been discovered. Medicinal chemistry efforts startingfrom optimizing SMART compound 1h. Chemical modifications of differentsubstituted aryl in “B” ring and linkages between “B” and “C” rings wereinvestigated based on biological evaluation against cancer cells invitro. SAR studies revealed that optimal “B” rings include pyridine(1c), thiophene (1f), and furan (1d) which maintain excellent in vitropotency. Replacing carbonyl linker with cyanoimine (2j) between “B” and“C” ring will increase the activity. Structure modifications to increaseaqueous solubility and bioavailability were performed. Introducing anamino between “A” and “B” rings gave us compounds 5a-c, which showedsimilar in vitro antiproliferative potency against tested cancer cellsas well as MDR(+) and MDR(−) cell lines, furthermore, the solubility andin vivo bioavailability were improved greatly over those of the 1h.Therefore, these new anti-tubulin compounds represent a new family ofcompounds that may be very useful in the treatment of cancer.

Example 12 Antiproliferative Activity of Compounds of this Invention

The antiproliferative activity of analogs prepared by the methods of theinvention are shown in Tables 6 and 6A.

TABLE 6 IC₅₀ ± SEM (nM) MES- MES- NCI/ADR- ID LNCaP PC-3 DU 145 PPC-1A375 B16-F1 WM164 SA SA/Dx5 OVCAR-8 RES Paclitaxel 1.7 4.8 5.1 2.3 12 172.7 6.6 4.7 6263 Vinblastine 1.1 2.1 1.8 1.1 1 4.7 1.4 16 3.9 582Colchicine 16 11 10 20 20 29 8.4 22 17 1113 1k 101 101 140 84 100 245220 2k 6 13 12 8 33 43 11 19 34 12 2m 19 8.7 6.9 6.2 11 21 2n 101 131143 99 210 290 2o 65 73 121 73 38 42 2p >10000 2385 1899 1079 2200 165602q >10000 >10000 >10000 >10000 >20000 >20000 5c-HCl 53 53 70 43 6d 703908 1637 929 *ND: not determined

TABLE 6A IC₅₀ (nM) Structure ID LNCaP PC-3 DU 145 PPC-1 A375 B16-F1WM164 MES-SA MES-SA/Dx5 OVCAR-8 NCI/ADR-RES

 8 346 704 580 230 318 570 404

 9 ~10000 ~10000 ~10000 ~10000

10 658 786 839 701 1111 2127 661

11 >10000 >10000 ~10000 ~10000 3470 4900 4700

12 >10000 >10000 >10000 >10000 >10000 >10000

13 >10000 >10000 >10000 >10000 >10000 >10000 >10000

14 >10000 >10000 >10000 >10000 >10000 >10000

16 >10000 >10000 >10000 >10000 15200 6900

17 2100 1900 2600 1300 4300 9800

18 ~10000 ~10000 ~10000 ~10000

19 >20000 >20000 >20000 >20000 >20000 >20000

20 1452 >10000 642 633 2300 3100 1300

21 314 403 435 216 383 924 408

22 >20000 >20000 >20000 >20000 >20000 >20000

23 ~10000 ~10000 ~10000 ~10000

24 >10000 >10000 >10000 >10000 >10000 >10000 >10000

25 48 44 24 13 20 38

26 23 16 16 15 11 14

29 1788 >10000 >10000 >10000 >10000 >10000

30 >10000 >10000 >10000 >10000 >10000 >10000

32 1664 2291 4601 1170 2700 >10000 2600

33 >2000 >2000 >2000 >2000 9800 >20000

34 >10000 >10000 >10000 >10000 >10000 >10000 >10000

35 1500 40100 21900 15000

39 4300 32500 16800 21400

40 13400 19600 18400 6200

41 15750 18170 17040 >20000

42 43590 23790 24880 >20000 43 12690 14720 17210 >20000

17ya 12 10 17 21 17.35 32.94 12.08

17yac 233.7 148.3 592.1 208.9 481.2 538.7 467.6

15xaa 1068 2628 5917 4575 1800 1390 1700

16xaa >10000 >10000 >10000 >10000 >10000 >10000 >10000

Example 13 Biological Evaluation of Isoquinoline Derivatives of thisInvention Cell Culture.

LNCaP, PC-3, DU-145, PPC-1, MES-SA, and MES-SA/DX5 were originallyobtained from ATCC (Rockville, Md.). All cells obtained from ATCC wereimmediately expanded and frozen down such that all cell lines could berestarted every 2-3 months from a frozen vial of the same batch ofcells. For the in vivo xenograft studies, PC-3 was authenticated atResearch Animal Diagnostic Laboratory (Columbia, Mo.) within four monthsbefore studies. Inter-species contamination was tested by PCR and theidentity of the cell lines was verified by generating a genetic profile.MES-SA and MES-SA/DX5 were maintained in McCoy's 5A Medium containing 2mM L-glutamine supplemented with 10% fetal bovine serum (FBS). All othercells were maintained in RPMI-1640 medium with 2 mM L-glutamine and 10%FBS.

Growth Inhibition Assay.

The cytotoxic or antiproliferative activity of test compounds wasinvestigated in several cell lines using the sulforhodamine B (SRB)assay. Cultured cells were plated into 96-well plates and incubated withmedium containing different concentrations of the test compounds for 96h. Cells were stained with SRB solution. The optical density wasdetermined at 540 nm on a microplate reader (Dynex Technologies,Chantilly, Va.). Plots of percent inhibition of cell growth versus drugconcentration were constructed, and the concentration that inhibitedcell growth by 50% relative to the untreated control (IC₅₀) wasdetermined by nonlinear least squares regression using WinNonlinsoftware (Pharsight Corporation, Cary, N.C.).

Cell Cycle Analysis.

Cell cycle distribution was determined by propidium iodide (PI)staining. Treated cells were washed with PBS and fixed with 70% ice-coldethanol overnight. Fixed cells were then stained with 20 μg/mL of PI inthe presence of RNase A (300 μg/mL) at 37° C. for 30 min. Cell cycledistribution was analyzed by fluorescence-activated cell sorting (FACS)analysis core services at the University of Tennessee Health ScienceCenter, TN.

In Vitro Metabolism Studies.

For both phase I, the incubation mixture, in 65 mM potassium phosphatebuffer (pH 7.4), consisted of 1 mg/mL liver microsomal proteins, 3 mMNADPH, and 0.5 μM test compound. The concentration of methanol (used fordissolving the substrate) was 1% (v/v). Total volume of the incubationwas 200 μL and the reaction mixtures were incubated at 37° C. Togenerate the stability curves for test compounds different incubationswere stopped at 10, 20, 30, 60, and 90 minutes for analysis of compoundsremaining. All reactions were stopped by the addition of 200 μL ice-coldacetonitrile. Subsequently, the samples were then centrifuged at 3000 gfor 5 min and supernatant was analyzed by LC-MS/MS.

Pharmacokinetic Studies in Mice.

Male ICR mice (5-6 weeks, 20-25 g) were used. For 6a, 6b, and 6c a doseof 5 mg/kg was administered via the i.v., i.p., and p.o. route. I.v.doses were administered via the tail vein. Oral doses were administeredby gavage. At each time point, three to four mice were euthanized byisoflurane (Baxter Healthcare, Deerfield, Ill.) and blood samples (up to600 μL each) were taken from the posterior vena cava. Plasma sampleswere stored at −20° C. prior to analysis. Plasma proteins wereprecipitated by the addition of acetonitrile (150 μL, containing theinternal standard) to 100 μL of mouse plasma. Samples were vortexed andthen centrifuged at 8000 g for 10 min. The supernatant was transferredto a clean vial for injection into the mass spectrometer for analysis.

In Vivo Antitumor Efficacy Study.

PC-3 cells (2.5×10⁶ cells/site) plus Matrigel (BD biosciences, San Jose,Calif.) were injected subcutaneously into flanks of male nu/nu mice.Tumor size was measured using calipers every 2-4 days and calculated asV=π/6×(length)×(width)². When tumors reached a volume of approximately100-150 mm³, drug treatment was initiated. The control group was treatedwith vehicle (20% Captex200 in Tween80). During the treatment, tumorsize and body weights were measured every 2-4 days.

White Blood Cell Counting.

Whole blood was obtained from nude mice at the end of efficacy study. Tocount white blood cells (WBC) using a hemacytometer, 10 μL of wholeblood sample was diluted with the 190 μL of 2% acetic acid. With properlight adjustment, the leukocytes appeared as dark dots on thehemacytometer. WBC in each sample was counted twice within one hoursfollowing dilution and average was calculated.

Results

TABLE 7 Anticancer efficacy of isoquinoline compounds in differentcancer cell lines and MDR cell lines mediated by P-glycoprotein IC₅₀(nM) 6a 6b 6c Vinblastine Docetaxel LNCaP 80.6 ± 17.1  98.1 ± 17.9 38.3± 9.7 3.4 ± 0.9 4.7 ± 1.3 PC-3 64.4 ± 12.2 71.8 ± 9.1 25.6 ± 8.3 1.4 ±0.3 6.3 ± 0.4 DU-145 91.7 ± 10.2 113.4 ± 21.4  46.6 ± 13.8 2.6 ± 1.0 5.2± 1.0 PPC-1 60.6 ± 3.4   47.9 ± 10.0 27.7 ± 4.5 1.1 ± 0.4 2.7 ± 1.0 P-gpMES-SA 78.2 ± 1.8  129.8 ± 38.0 35.6 ± 2.8 2.3 ± 0.8 5.9 ± 1.1MES-SA/DX5 119.4 ± 0.4  177.8 ± 32.8 59.2 ± 0.1 45.7 ± 5.3  76.4 ± 8.7 Resistance factor 1.5 1.4 1.7 20 13 NOTE: P-gp is over-expressed inMES-SA/DX5. The resistance factor (RF) was calculated as the ratio ofIC₅₀ values for the resistant cell subline to that of the parental cellline. All experiments were performed at least in three replicates.

TABLE 8 Compound 6a, 6b, and 6c arrested PC-3 cells in G₂M phase. G₂Mphase arrest EC₅₀ (nM) 6a 53.4 6b 91.9 6c 23.3

TABLE 9 Summary of half lives (phase I pathway) of 6a, 6b, and 6c inmouse, rat, hamster, rabbit, guinea pig, dog, monkey, and human livermicrosomes. T½ (min) 6a 6b 6c Mouse 3.4 10 13 Rat 12 9 14 Hamster 6 1120 Rabbit 17 16 16 Guinea pig 15 15 8 Dog 13 30 29 Monkey 16 13 9 Human32 40 47

TABLE 10 Summary of pharmacokinetic properties of compound 6a, 6b, and6c in mice. 6a 6b 6c

MW 410.5 359.4 338.4 IV CL (mL * min⁻¹kg⁻¹) 5 mg/kg 51 14 30 IV V_(d)(L * kg⁻¹) 5 mg/kg 2.3 1.1 1.8 IP C_(max) (ng/mL) 5 mg/kg 678.4 15001100 IP AUC (min * μg/mL) 5 mg/kg 59 218 55 IP Bioavailability F_(ip) %60 60 33 PO C_(max) (ng/mL) 5 mg/kg 6.7 50 50 AUC (min * μg/mL) 5 mg/kg5 7 4 PO Bioavailability F_(po) % 5 2.1 2.7

Efficacy and tolerability of 6b and 6c was measured in xenograft modelsafter i.p. injection (FIG. 34). PC-3 xenografts were treated withvehicle (qd), 6b (40 mg/kg, qd), or 6c (40 mg/kg, qd) for 3 weeks.Dosing vehicles were composed of 20% Captex200 in Tween80. The tumorvolumes (mm³) were plotted against time and are the means±SD from eightanimals. The tumor volumes and survival rates or body weights are shownin FIG. 34A. The liver size (g) of each nude mouse was measured after 3weeks treatment and is shown in FIG. 34B. The number of white bloodcells was counted in whole blood collected from animal after 3 weekstreatment and is shown in FIG. 34C.

Example 14 Antiproliferative Activity of Selected ABI Compounds of thisInvention Cell Culture Cytotoxicity Assay Materials and Methods

The antiproliferative activity of the ABI compounds in three melanomacell lines (A375 and WM-164, human melanoma cell line; B16-F1, mousemelanoma cell line) and four human prostate cancer cell lines (LNCaP, DU145, PC-3, and PPC-1) were studied. All these cell lines were purchasedfrom ATCC (American Type Culture Collection, Manassas, Va.) except thePPC-1 cell line. MDA-MB-435 and MDA-MB-435/LCCMDR1 cells were kindlyprovided by Dr. Robert Clarke at Georgetown University School ofMedicine, Washington, D.C. Melanoma cells were cultured in DMEM (CellgroMediatech, Inc., Herndon, Va.) and prostate cancer cells were culturedin RPMI 1640 (Cellgro Mediatech, Inc., Herndon, Va.) supplemented with10% FBS (Cellgro Mediatech). Cultures were maintained at 37° C. in ahumidified atmosphere containing 5% CO₂. 1000 to 5000 cells were platedinto each well of 96-well plates depending on growth rate and exposed todifferent concentrations of a test compound for 48 h (fast growingmelanoma cells) or 96 h (slow growing prostate cancer cells) in three tofive replicates. Cell numbers at the end of the drug treatment weremeasured by the sulforhodamine B (SRB) assay. Briefly, the cells werefixed with 10% trichloroacetic acid and stained with 0.4% SRB, and theabsorbances at 540 nm were measured using a plate reader (DYNEXTechnologies, Chantilly, Va.). Percentages of cell survival versus drugconcentrations were plotted, and the IC₅₀ (concentration that inhibitedcell growth by 50% of untreated control) values were obtained bynonlinear regression analysis using GraphPad Prism (GraphPad Software,San Diego, Calif.).

Results

The results of the in vitro antiproliferative activities of thecompounds of this invention using three melanoma cell lines (one murinemelanoma cell line, B16-F1, and two human metastatic melanoma celllines, A375 and WM-164) and four human prostate cancer cell lines(LNCaP, PC-3, Du 145, and PPC-1) are summarized in Tables 11-13.

TABLE 11 In vitro growth inhibitory effects of compounds without A ringsubstitutions. IC₅₀ (nM) Structure ID R A375 B16-F1 WM164 LNCaP PC-3 Du145 PPC-1

12aa 12ab 12ac 12ad 12ae 12af 12ag 12ah 12ai 3,4,5-(OMe)₃ 4-OMe 3-OMe3,5-(OMe)₂ 3,4-(OMe)₂ 4-F 3-F 4-Me 3-Me   160 >10000 >10000  2800 >10000  580 >10000 >10000 >10000   120 >10000 >10000  5400 >10000  930 >10000 >10000 >10000   10 >10000 >10000  2100 >10000  630 >10000 >10000 >10000   152 >10000 >10000  3611 >10000  613 >10000 >10000 >10000   288 >10000 >10000  3274 >10000 2197 >10000 >10000 >10000   196 >10000 >10000  2590 >10000  846 >10000 >10000 >10000   133 >10000 >10000  2129 >10000  575 >10000 >10000 >10000

12aba 12aaa 4-OMe3,4,5-(OMe)₃ >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000>10000

10a 10x 10j H 4-NO₂4-OBn >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000 >10000>10000

From Table 11, compounds 12aa-12ai showed moderate activity with IC₅₀values in the μM range (average of all seven cell lines). The mostpotent compound of this series was 12aa with an average IC₅₀ value of160 nM. The removal of one of the methoxy groups from the3,4,5-trimethoxy on the C ring (12ad, 12ae) led to a significant loss ofactivity (IC₅₀>10 μM for 12ae and an average IC₅₀ of 3.1 μM for 12ad).Compound with 4-fluoro on the C ring (12af) also showed relatively goodactivity (IC₅₀=0.91 μM), a finding that has an important implication,because replacing the trimethoxy moiety with a 4-fluoro group mayprovide good activity and improved metabolic stability. The position ofthe fluorine on the C ring was critical for activity because a shiftfrom 4-fluoro to 3-fluoro resulted in a total loss of activity (IC₅₀>10μM for 12ag compared with 0.91 μM for 12af). This result suggested thata potential hydrogen bond donor is present close to the 4-position ofthis ring.

As clearly indicated in Table 11, the positions of the A and C ringswere critical. A simple shift of the C-ring moiety from position 4 toposition 1 in the imidazole ring (B ring) resulted in total loss ofactivity (IC₅₀>10 μM for 12aba, 12aaa, 10a, 10x, 10j).

TABLE 12 In vitro growth inhibitory effects of compounds withsubstitutions on A ring. IC₅₀ ± SEM (nM) ID R¹ R² A375 B16-F1 WM164LNCaP PC-3 Du 145 PPC-1 OVCAR-8 NCI/ADR-RES

12ba 12ca 12cb 12da 12db 12db-HCl 12dc 12ea 12eb 12fa 12fb 13fa 12ga12gb 12ha 12hb 12ia 12ib 13ea 12ja 12jb 12ka 12kb 12kc 12la 12pa 13ha12q 12v 12w Colchicine 4-F 4-OMe 4-OMe 4-Me 4-Me   4-Me 3,4,5-(OMe)₃3,4,5-(OMe)₃ 4-Cl 4-Cl 4-Cl 4-N(Me)₂ 4-N(Me)₂ 3,4-(OMe)₂ 3,4-(OMe)₂2-CF₃ 2-CF₃ 3,4,5-(OH)₃ 4-OBn 4-OBn 4-OH 4-OH 4-OH 4-Br 4-CF3 3,4-(OH)₂4-Et 4-CH(CH₃)₂ 4-C(CH₃)₃ 3,4,5-(OMe)₃ 3,4,5-(OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F  3,5-(OMe)₂-4-OH 3,4,5-(OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F 3,4,5-(OH)₃3,4,5-(OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F 3,4,5-(OH)₃3,4,5-(OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F 3-OH, 4,5-(OMe)₂ 3,4,5-(OMe)₃3,4,5-(OMe)₃ 3,4,5-(OH)₃ 3,4,5-(OMe)₃ 3,4,5-(OMe)₃ 3,4,5-(OMe)₃ 205 ±19  30 ± 5  31 ± 5  9 ± 2 143 ± 12  108 ± 11    105  4800 >10000 43 ± 5 52 ± 4   3900 82 ± 9  56 ± 7  113 ± 14   10000 >10000 >10000 >10000 5200 93 ± 8   1600  10000  10000   32    163.1 >10000 ND ND ND 20 ± 3 320 ± 41  108 ± 12  63 ± 7  46 ± 5  222 ± 10  297 ± 23   387 >10000 >10000 168 ± 14  73 ± 6   1810 361 ± 29  129 ± 11  1400 ±200   4210 >10000 >10000 >10000  10000 117 ± 16   2400 >10000  5600   74   468.7 >10000 ND ND ND 29 ± 5  73 ± 8  31 ± 4  28 ± 3  8 ± 2 156 ± 19 112 ± 9    123 >10000 >10000 26 ± 3  74 ± 9  2100 80 ± 11 62 ± 8  191 ±18  1400 >10000 >10000 >10000  5500 90 ± 12  1800 >10000  6400   36  175 >10000 ND ND ND ND 98 ± 2  31 ± 1  28 ± 2  12 ± 1  45 ± 2  ND  134 >10000 >10000 24 ± 1  49 ± 2   10000 58 ± 2  57 ± 6  121 ± 10  2533 >10000 >10000 >10000  2786 44 ± 7  ND  10000     34   134 ND    9  171   423 16 ± 4  169 ± 12  45 ± 1  31 ± 2    9 ± 0.4 56 ± 3  ND  127 >10000 >10000 35 ± 1  81 ± 2   10000 92 ± 4  81 ± 3  203 ± 7  10000 >10000 >10000 >10000  10000  79 ± 0.4 ND >10000     36   127 ND13(PC3/TXR=8   136   436 11 ± 1  132 ± 24   48 ± 0.5 41 ± 38  15 ± 0.578 ± 5  ND   174 >10000 >10000  36 ± 0.4 65 ± 1   10000 95 ± 1   72 ±0.4 168 ± 15   10000 >10000 >10000 >10000  10000 60 ± 3  ND >10000    49   174 ND 25(DU145/TXR=20)   482  1698 10 ± 2  81 ± 1   34 ± 0.3 29± 1   11 ± 0.1 54 ± 1  ND   110 >10000 >10000  26 ± 0.2 52 ± 1  >10000 67 ± 0.7  45 ± 0.3 117 ± 1  2172 ± 48  >10000 >10000 >10000  2844  43 ±0.2 ND >10000     33   110 ND   15   173   294 20 ± 1                   47                   19 ND—not determined

From Table 12 compounds with 3,4,5-trimethoxy and 4-fluoro substitutionson the C ring showed good activity with different substitutions on the Aring. These compounds demonstrated excellent antiproliferative activitywith IC₅₀ values as low as 8.0 nM on WM164 cell line (12da). In general,compounds incorporating a single substituent on the para-position of theA ring were more potent as can be seen from the activities of 12ca,12cb, 12da, 12db, 12fa, 12fb, 12ga, and 12gb (IC₅₀=7.9-110 nM). 12db-HClsalt (IC₅₀=172 nM) showed slightly diminished activity compared with thecorresponding free base 12db (IC₅₀=109 nM). Compound 12fb (IC₅₀=63.7nM), with a single halogen substituent in the para-position of the A andC rings, demonstrated potent and was devoid of a methoxy moiety.Compounds with 3,4,5-trimethoxy substituents on the A ring lost activitycompletely (IC₅₀>10 μM for 12ea, 12eb), suggesting very differentbinding environments near the A ring and C ring. Removal of the5-methoxy substituent from the A-ring improved activity significantly(IC₅₀=330 nM and >10 μM for 12ha, 12ea respectively). Demethylation ofthe 3,4,5-trimethoxy decreased activity sharply from 43 nM (12fa) to3.89 μM (13fa). Similar results were observed for 13ea, 12ka, 12kb, and13ha due to the demethylation of substituents on either the A or C ring.Electron-donating groups (4-methoxy, 4-dimethylamino, 4-methyl) andelectron-withdrawing groups (4-chloro, 2-trifluoromethyl) on the A ringdid not show substantial differences in activity. The introduction of atrifluoromethyl group at the ortho position of the A ring causedcomplete loss of activity (IC₅₀>10 μM for 12ia, 12ib). The presence of abenzyloxy group at the para position of A ring (IC₅₀=75 nM for 12jb)resulted in a 440-fold increase in activity when compared with thepara-hydroxy compound 12kb (IC₅₀=33 μM). It is worthwhile to note thatcompound 12jb, with the 4-fluoro in the C ring, has better activity thandoes its counterpart 12ja, which has a 3,4,5-trimethoxy group in the Cring (IC₅₀ is 75 nM for 12jb, and 7.3 μM for 12ja).

TABLE 13 In vitro growth inhibitory effects of compounds with protectionon B ring. IC₅₀ ± SEM (nM) Structure ID R¹ R² R³ A375 B16-F1 WM164 LNCaPPC-3 Du 145 PPC-1

11ab 11ac 11ah 11af 11ag 11cb 11db 11ea   11eb   11fb 11ga   11gb   11ha  11hb   11ia   11ib 11jb 12dab   12cba 12daa   12gba H H H H H 4-OMe4-Me 3,4,5- (OMe)₃ 3,4,5- (OMe)₃ 4-Cl 4- N(Me)₂ 4- N(Me)₂ 3,4- (OMe)₂3,4- (OMe)₂ 2-CF₃   2-CF₃ 4-OBn 4-Me   4-OMe 4-Me   4- N(Me)₂ 4-OMe3-OMe 4-Me 4-F 3-F 4-F 4-F 3,4,5- (OMe)₃ 4-F   4-F 3,4,5- (OMe)₃ 4-F  3,4,5- (OMe)₃ 4-F   3,4,5- (OMe)₃ 4-F 4-F 3,4,5- (OMe)₃ 4-F 3,4,5-(OMe)₃ 4-F SO₂Ph SO₂Ph SO₂Ph SO₂Ph SO₂Ph SO₂Ph SO₂Ph SO₂Ph   SO₂Ph  SO₂Ph SO₂Ph   SO₂Ph   SO₂Ph   SO₂Ph   SO₂Ph   SO₂Ph SO₂Ph Me   Me CH₂Ph  SO₂PhOMe >10000 >10000 >10000 630 ± 72  >10000 36 ± 5  113 ±14  >10000    3840   88 ± 9  162 ± 13    55 ± 7    192 ± 15    960 ± 59   >10000   >10000 64 ± 7    32   >10000      ~100 >10000 >10000 >10000946 ± 86  >10000 71 ± 8  287 ± 31  >10000   >10000   107 ± 12  1200 ± 90242 ± 26    970 ± 68    2000 ± 400 >10000   >10000 110 ± 15    134  >10000      ~100 >10000 >10000 >10000 596 ± 61  >10000 43 ± 6  107 ±14  >10000   >10000   70 ± 6  308 ± 32    56 ± 4    139 ± 15    1400 ±30    >10000   >10000 48 ± 5    40   >10000     ~100 >10000 >10000 >10000   573 >10000 31 ± 2  55 ± 3  >10000   >10000  48 ± 1  62 ± 2    56 ± 6    114 ± 6    1915 ± 77    >10000   >10000 35± 1    32   >10000     683.2       73.2 >10000 >10000 >10000 2233 >10000 33 ± 2  80 ± 1  >10000   >10000   76 ± 2  93 ± 6    83 ± 3   197 ± 9     10000   >10000   >10000  75 ± 0.5   46   >10000    465.8      44.14 >10000 >10000 >10000   846 >10000 52 ± 3  80 ± 1  >10000  >10000   64 ± 1  99 ± 2     74 ± 0.5   144 ± 29     3312   >10000  >10000 58 ± 1    36   >10000  1501      129.4 >10000 >10000 >10000  575 >10000  32 ± 0.7 57 ± 1  >10000   >10000   54 ± 1   72 ± 0.4    48± 0.3   117 ± 2    1441 ± 49    >10000   >10000  38 ± 0.2   28   >10000   777.9       63.4

TABLE 13A Reversed aryl benzoyl imidazole (RABI)-inhibitory effects PC3/DU145/ LNCaP PC3 TXR PPC1 DU145 TXR Structure ID R₄ R₉ R₁₂ (nM) (nM)(nM) (nM) (nM) (nM)

70a 70b 70c 70d 70e 70f 70g 70h 70i 70j 70k 70l 70m 70n 70o 70p 70ab70ac 70ad —H —F —Cl —Br —CF₃ —CH₃ —OCH₃ —N(CH₃)₂ —OH —H —H —H —H —H —H—H —H —H   —H —H —H —H —H —H —H —H —H —H —H —H —H —Me —Et —Bn-cyclopentyl n-Pr —CH(CH₃)₂  

—H —H —H —H —H —H —H —H —H —Me —Et -n-Pr —H —H —H —H —H —H   —H   6  114 22  15  47  13  30  96  219  938 2029 3094  10  29  67  51    49.4   62.2      19.5   14  196   64   33   93   19   61  117  155  1617 3654 12360   16   25   72   56    25.6    52.5      11.1  4 — 25 17 4610 25 — — — — —   7.5 20 — — — —   —   13   13   51   30   75   18   54 120  122  860  2078 11410   13   30   77   63    9.8    15.0      7.8   21.5  353  125   66  210   30  210  263  518  2001  5079 16350   26  66  160  167    71.6    114.1      36.3   22.9 — 121  63 202  21 111 —— — — —  27  66 — —

TABLE 13B Reversed aryl benzoyl imidazole (RABI)-inhibitory effectsLNCaP PC3 PPC1 DU145 Structure ID R₁ R₂ R₃ R₄ R₅ R₆ (nM) (nM) (nM) (nM)

70q 70r 70s 70t 70u 70v 70w 70x 70y 70z 70aa OMe F Cl Br CF₃ CH₃ OMe HOMe Br H OMe H H H H H H H H H H OMe H H H H H H H H H H OMe F Cl Br CF₃CH₃ OMe OMe OMe OMe H OMe H H H H H H OMe OMe OMe H OMe H H H H H H OMeOMe OMe H >50000 >50000 >50000  16930 >50000  3762  6410    195.4   708.5   131 >50000 >50000 >50000 >50000  18940 >50000  5159  23370   631.5  10390   371 >50000 >50000 >50000 >50000  13210 >50000  2405 38105    408.5  5685   107 >50000 >50000 >50000 >50000  25490 >50000 6541  9389  1301 >50000   430 >50000

From Table 13, compounds with a phenylsulfonyl protection group attachedto the nitrogen of the imidazole ring (11cb, 11db, 11fb, 11ga, 11gb,11ha, 11jb) were also very active with IC₅₀ in the nM range (Table 13).Generally the activities of these compounds are comparable to theircorresponding unprotected counterparts as exemplified by comparing theactivities of 11cb (43 nM), 11db (111 nM), 11fb (72 nM), 11ga (285 nM),11gb (87 nM), 11ha (268 nM), and 11jb (61 nM) with their correspondingunprotected counterparts 12cb (36 nM), 12db (109 nM), 12fb (64 nM), 12ga(131 nM), 12gb (72 nM), 12ha (330 nM), and 12jb (75 nM). Other compounds(11ab-11ag, 11ea, 11eb, 11hb, 11ia, and 11ib, 1-50 μM) were generallymuch less active, also in line with their counterparts (12ab-12ag, 12ea,12eb, 12hb, 12ia, and 12ib, 1-50 μM).

The PC3 cell cycle distributions of compounds of this invention arepresented in FIG. 39.

Method Cell Cycle Analysis.

Cell cycle distribution was determined by propidium iodide (PI)staining. Treated cells were washed with PBS and fixed with 70% ice-coldethanol overnight. Fixed cells were then stained with 20 μg/mL of PI inthe presence of RNase A (300 μg/mL) at 37° C. for 30 min. Cell cycledistribution was analyzed by fluorescence-activated cell sorting (FACS)analysis core services at the University of Tennessee Health ScienceCenter, TN.

Result

Reversed ABIs (RABIs) demonstrated by cell cycle analysis that theyarrest cells in the G2/M phase. Compounds 12q, 70a, 70f, and 70m weretreated on PC3 cells for 24 h (FIG. 39) and the distribution of PIstained cells was investigated by FACS analysis. Four differentconcentrations—1, 10, 50, and 100 nM—of each compound were chosen toexamine the dose effect. In the vehicle treated group, about 18% of PC3cells were distributed in the G2/M phase. RABIs increased the proportionof cells in G2/M phase up to 70% approximately in aconcentration-dependent manner. The potency of the differentconcentrations in arresting cells in the G2/M phase positivelycorrelated with in vitro cell growth inhibitory activity.

Example 15 Activity of Aryl-Benzoyl-Imidazole (ABI) Compounds inDrug-Resistant Melanoma Cells

P-glycoprotein (Pgp)-mediated drug efflux represents a major mechanismfor cancer cells to prevent the build up of effective anticancerintracellular drug concentrations. The activity of the ABI compoundswere compared against multidrug-resistant (MDR) melanoma cells(MDA-MB-435/LCCMDR1) and their parental nonresistant cancer cells(MDA-MB-435). Although MDA-MB-435 was originally designated as a breastcancer cell line, it has been shown definitively to originate from theM14 melanoma cell line. Compounds 12da, 12fb, 12cb, 11cb, and 11fbtogether with other tubulin-targeting agents including colchicine,paclitaxel, and vinblastine were tested on both the MDR melanoma cellline and its parental melanoma cell line (Table 14A). Paclitaxel andvinblastine are clinically used anticancer drugs known to target celltubulin. Although colchicine is not an FDA-approved drug for cancertreatment, its prodrug, ZD6126, is in clinical trial for solid tumors.Bortezomib is the first therapeutic proteasome inhibitor and wasapproved in 2003 by the FDA for use in multiple myeloma. ABT-751 isknown to target the tubulin colchicine binding site. It is a promisingdrug candidate in clinical trial for children with relapsed orrefractory neuroblastoma. Compounds 12da, 12fb, 12cb, 11cb, 11fb hadmuch better resistance indices (3.0 for 12da, 0.9 for 12fb, 1.3 for12cb, 0.8 for 11cb, 0.7 for 11fb) than colchicine (65.8), paclitaxel(69.3), and vinblastine (27.5). Although colchicine, paclitaxel, andvinblastine showed excellent activity in nonresistant melanoma celllines (0.5-10 nM), these compounds were significantly less potent in theMDR melanoma cell line (277-658 nM). In contrast, 12cb, 11cb, 11fb hadessentially equivalent potency on both MDR (15 nM, 38 nM, 30 nM, 30 nM,35 nM for 12da, 12fb, 12cb, 11cb and 11fb respectively) and nonresistantmelanoma cell lines (5 nM, 41 nM, 24 nM, 38 nM, 50 nM for 12da, 12fb,12cb, 11cb and 11fb respectively). Compound 12da was more active thanpaclitaxel and colchicine on A375 and WM-164 cells.

TABLE 14A In vitro growth inhibitory effects of the ABI compounds incomparison to other anticancer drugs on multidrug-resistant melanomacell line (MDR cell) and the matching sensitive parent cell line (NormalMelanoma cell). IC₅₀ ± SEM (nM) (n = 3) Tubulin Compound WM- bindingMDA- MDA-MB-435/ Resistance ID A375 B16-F1 164 (μM) MB-435 LCC6MDR1index* 12da  9 ± 2 46 ± 5  8 ± 2 0.2 ± 0.1  5 ± 1 15 ± 2 3.0 12fb 52 ± 473 ± 6 74 ± 9 3.9 ± 2.1 41 ± 2 38 ± 2 0.9 12cb 31 ± 5 63 ± 7 28 ± 3 3.4± 1.5 24 ± 2 30 ± 4 1.3 11cb 36 ± 5 71 ± 8 43 ± 6 ND 38 ± 3 30 ± 2 0.811fb 88 ± 9 107 ± 12 74 ± 8 ND 50 ± 6 35 ± 3 0.7 Paclitaxel 12 ± 3 17 ±2 18 ± 3 N/A  4 ± 1 277 ± 41 69.3 Vinblastine  1.1 ± 0.2  4.7 ± 0.7  0.6± 0.1 ND  0.4 ± 0.1 11 ± 1 27.5 Colchicine 20 ± 3 29 ± 5 10 ± 2 1.8 ±0.5 10 ± 1 658 ± 50 65.8 Bortezomib  8 ± 1 24 ± 2  8 ± 1 ND ND ND NDABT-751 1111 ± 108 2127 ± 351 661 ± 56 ND ND ND ND *Resistance indexeswere calculated by dividing IC₅₀ values on multidrug-resistant cell lineMDA-MB-435/LCC6MDR1 by IC₅₀ values on the matching sensitive parentalcell line MDA-MB-435. Abbreviations: N/A, value not available; ND, notdetermined.

TABLE 14B Anticancer efficacy and colchicine site binding affinity ofABIs in different cancer and MDR cell lines with different resistancemechanisms. ABIs showed excellent potency against all tested melanomacell lines including highly metastatic and multidrug resistant celllines. High binding affinity of ABIs to the colchicine binding site intubulin confirmed their target inside cells. IC₅₀ ± SEM (nmol/L) (n = 3)12cb 12da 12fb Paclitaxel Vinblastine Colchicine ABT-751 SN-38 A375 31 ±5 9 ± 2 52 ± 4 12 ± 3   1 ± 0.1 20 ± 3  685 ± 108 ND A375MA2 44 ± 5 8 ±1 55 ± 4  8 ± 1   1 ± 0.2 18 ± 2 265 ± 36 ND B16-F1 63 ± 7 46 ± 5  73 ±6 17 ± 2  5 ± 1 29 ± 5 2127 ± 351 ND WM-164 28 ± 3 8 ± 2 74 ± 9 18 ± 3 0.6 ± 0.1 10 ± 2 661 ± 56 ND MDR1 MDA-MB- 24 ± 2 5 ± 1 41 ± 2  4 ± 1 0.4 ± 0.1 10 ± 1 417 ± 23 ND 435* MDA-MB- 30 ± 4 11 ± 2  38 ± 2 277 ± 411 ± 1 658 ± 50 577 ± 31 ND 435/LCC6MDR1 (1) (2) (1) (69) (28) (66) (1)OVCAR-8* 25 ± 2 11 ± 1  45 ± 2   10 ± 0.2   2 ± 0.1 12 ± 1 785 ± 17   2± 0.2 NCI/ADR- 13 ± 1   5 ± 0.1 20 ± 6 5109 ± 170 570 ± 84 737 ± 51 864± 42 10 ± 1 RES (0.5) (0.5) (0.4) (511) (285) (61) (1) (5) MRP HEK293-12 ± 2 9 ± 1   54 ± 0.3   9 ± 0.3   5 ± 0.1   3 ± 0.4 645 ± 153   3 ±0.4 pcDNA3.1* HEK293- 16 ± 2 8 ± 1 33 ± 7 30 ± 3 24 ± 1   5 ± 0.1 717 ±28    9 ± 0.04 MRP1 (1) (0.9) (0.6) (3) (5) (2) (1) (3) HEK293- 14 ± 4  8 ± 0.3  39 ± 12 37 ± 2 28 ± 2   3 ± 0.3 747 ± 7    7 ± 0.1 MRP2 (1)(0.9) (0.7) (4) (6) (1) (1) (2) BCRP HEK293- 17 ± 1 8 ± 1 23 ± 3 50 ± 125 ± 1   5 ± 0.1 653 ± 72 123 ± 28 482R2 (1) (0.9) (0.4) (6) (5) (2) (1)(41) Tubulin binding  3 ± 1 0.2 ± 0.1  4 ± 1 N/A ND  2 ± 1 3.1⁺⁺ ND(μM)⁺ Notes: *parental cell line to drug resistant cell subline; MDR1were overexpressed in MDA-MB-435/LCC6MDR1 and NCI/ADR-RES; MRP1, MRP2and BCRP were overexpressed in HEK293-MRP1, HEK293-MRP2, andHEK293-482R2. The resistance indexes (numbers in the parenthesis) werecalculated by dividing IC₅₀ values on the resistant cell subline by thatof the matching parental cell line. ⁺IC₅₀ for tubulin binding wascalculated from [³H]colchicine competition-binding scintillationproximity assay. ⁺⁺binding affinity reported in the literature forABT-751. Abbreviations: N/A, not applicable since they bind to tubulinat different sites.

TABLE 14C Anti-proliferative activity of methylene linked compounds(aryl-benzyl-imidazoles) in melanoma cells. IC50 ± SEM (μm) MDA-MB-Structure ID R₁ R₂ R₃ A375 MDA-MB-435 435/LCC6MDR1

102a 102b 102c 102d 102 e Colchicine H F H H H N/A 3,4,5-OMe)₃3,4,5-OMe)₃ 3,4,5-OMe)₃ 3,4,5-OMe)₃ 3,4,5-OMe)₃ N/A H Me Et n-Pr Ph N/A10.204 ± 0.392  >50 ND ND ND 0.024 ± 0.003 ND ND >50 10.951 ± 0.037  >500.011 ± 0.002 ND ND >50 15.949 ± 0.012  >50 0.643 ± 0.009 *N/A = notapplicable ND = not determined

TABLE 14D Anti-proliferative activity of aryl-benzoyl-imidazoles inmelanoma cells. IC50 ± SEM (μm) MDA-MB- MDA-MB- Structure ID R₁ R₂ R₃A375 435 435/LCC6MDR1

12q 12v 12w 4-Et 4-iPr 4-tBu 3,4,5-(OMe)₃ 3,4,5-(OMe)₃ 3,4,5-(OMe)₃ H HH 0.0014 ± 0.005  ND ND 0.107 ± 0.005 0.312 ± 0004  3.691 ± 0.006 0.027± 0.003 0.250 ± 0.004 3.074 ± 0.005

70aa 70a 70x 70q H H 3,4,5-(OMe)₃ 3,4,5-(OMe)₃ H 3,4,5-(OMe)₃ H3,4,5-(OMe)₃ N/A N/A N/A N/A ND ND ND ND >50 0.079 ± 0.003 4.605 ± 0.0070.149 ± 0.003 >50 0.043 ± 0.002 5.770 ± 0.006 0.211 ± 0.005 *N/A = notapplicable ND = not determined

The results of Table 14A showed that cell line MDA-MB-435/LCCMDR1 wasvery resistant to colchicine, paclitaxel, and vinblastine. But the ABIsof this invention showed equal potency to the drug-resistant cell lineand the sensitive parent cell line. This result strongly suggests thatABIs are not substrates for P-gp. Thus, they overcame the multidrugresistance found in MDA-MB-435/LCCMDR1 cells. The dose response curvesare shown in FIG. 21 for 12fb, 12da, and 12cb. Table 14B exploresfurther the resistance mechanisms for paclitaxel, SN-38, vinblastine,and colchicine as compared to the ABIs 12cb, 12da, and 12fb. MRP andBCRP conferred moderate resistance to paclitaxel (resistance indexes of4 and 6, respectively), vinblastine (resistance indexes of 6 and 5,respectively), and BCRP conferred significant resistance to SN-38(resistance index of 41). However, none of the ABIs were susceptible toMRP- or BCRP-mediated resistance (resistance indexes ranged from 0.4 to1.0). ABT-751, like the ABIs, was not susceptible to MDR1, MRP, or BCRP.

Example 16 In Vitro Microtubule Polymerization Assay Materials andMethods

Bovine brain tubulin (0.4 mg) (Cytoskeleton, Denver, Colo.) was mixedwith 10 μM of the test compound and incubated in 110 μl of generaltubulin buffer (80 mM PIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, and 1 mM GTP) atpH 6.9. The absorbance at 340 nm was monitored every 1 min for 15 min bythe SYNERGY 4 Microplate Reader (Bio-Tek Instruments, Winooski, Vt.).The spectrophotometer was set at 37° C. for tubulin polymerization.

Results

The inhibition of tublin polymerization by Aryl-Benzoyl-Imidazole (ABI)compounds was examined. Bovine brain tubulin (>97% pure) was incubatedwith three potent ABI compounds, 12cb, 12da, and 12db at a concentrationof 10 μM, to determine the effect of these ABI compounds on tubulinpolymerization (FIG. 22). Tubulin polymerization was completelyinhibited by compound 12da, while ˜80% inhibition was observed duringincubation with compounds 12cb and 12db.

This microtubule destabilization effect was similar to that ofcolchicine and vinblastine but was opposite to that of paclitaxel. Theresults not only confirmed that ABIs can directly interact with tubulinbut also suggested that they may share the same binding site withcolchicine (or vinblastine).

Example 17 Melanoma Inhibition In Vitro Materials and Methods

B16-F1 melanoma cells were plated at a colony-forming density (2000cells per well on six-well plates) on top of 0.8% base agar. Cells weregrown in 0.4% agar together with DMEM medium supplemented with fetalbovine serum and an antibiotic-antimycotic solution at 37° C. in anatmosphere of 95% air and 5% CO₂. Cells were treated with compounds12da, 12cb and 12fb at different concentrations (20, 100, and 500 nM).Compounds were added to the media from 1 mM DMSO stock solutions, and acorresponding dilution of DMSO was used as control. Cells were grown for14 days. Plates were photographed, and the number of colonies wasmeasured by Artek 880 Automated Colony Counter (Artek SystemsCorporation, Farmingdale, N.Y.).

Results

Four representative photos are shown in FIG. 23. After 14 days ofincubation, about 130 detectable colonies (diameter larger than 100 μm)were formed in controls (no treatment).

Compounds 12cb and 12da effectively inhibited B16-F1 melanoma colonyformation even at the lowest tested concentration, 20 nM (p<0.05compared with control). 12fb showed effective inhibition at 100 nM. Allthree tested compounds showed complete inhibition of colony formation at0.5 μM, further proving ABIs' antimelanoma efficacy.

Example 18 In Vivo Anti-Tumor Activity Materials and Methods

Animals:

Female C57/BL mice, age 4-6 weeks, were purchased from HarlanLaboratories (Harlan Laboratories Inc., Indianapolis, Ind.). The animalhousing met the Association for Assessment and Accreditation andLaboratory Animal Care specifications. All of the procedures wereconducted in accordance with guidelines of our Institutional Animal Careand Use Committee.

In Vivo Evaluation of Efficacy.

Mouse melanoma B16-F1 cells were prepared in FBS-free DMEM medium(Cellgro Mediatech) at a concentration of 5×10⁶ viable cells/mL. Thecell suspension (100 μL) was injected subcutaneously in the right dorsalflank of each mouse. When tumor size reached about 100-150 mm³, about 7days after cell inoculation, all mice bearing tumors were divided intocontrol and treatment groups based on tumor size (n=5 per group). Eachgroup had similar average tumor size. Mice in control groups (negativecontrol) were injected intraperitoneally with 50 μL vehicle solutiononly or DTIC at 60 mg/kg (positive control) once daily. Tumor volume wasmeasured every 2 days with a traceable electronic digital caliper(Fisher Scientific, Inc., Pittsburgh, Pa.) and calculated using theformula a×b²×0.5, where a and b represented the larger and smallerdiameters, respectively. Tumor volume was expressed in cubicmillimeters. Data were expressed as mean±SE for each group and plottedas a function of time. Percentage tumor reduction at the conclusion ofthe experiment (14 days after starting treatment) was calculated withthe formula 100-100×[(T−T₀)/(C−C₀)], where T represents mean tumorvolume of a treated group on a specific day, T₀ represents mean tumorvolume of the same group on the first day of treatment, C representsmean tumor volume of a control on a specific day, and C₀ represents meantumor volume of the same group on the first day of treatment. Animalactivity and average body weight of each group were monitored during theentire experiment period to assess compound toxicity. At the end oftreatment, all mice were euthanized by CO₂ followed by cervicaldislocation, and tumors were harvested for further studies.

Results

To evaluate efficacy of ABI analogs in vivo, we tested the antitumoractivity of compound 12cb on mice melanoma B16-F1 xenograft. againstDTIC, the gold standard in malignant melanoma treatment, was used as apositive control (FIG. 24A). Twenty female C57/BL mice were divided intofour groups: a vehicle control group, a DTIC (60 mg/kg) treatment group,a 12cb (10 mg/kg) treatment group, and a 12cb (30 mg/kg) treatmentgroup. Each mouse was injected with 0.5 million B16-F1 melanoma cellssubcutaneously. Seven days after tumor inoculation, treatment startedwith each compound injected intraperitoneally daily (FIG. 24). Tumorvolume was significantly (p<0.05) reduced 47%, 51%, and 73% for 12cb (10mg/kg), DTIC (60 mg/kg), and 12cb (30 mg/kg), respectively, after 14days of treatment. No significant weight loss was observed in any of thetreatment groups during the experiment.

Two dose levels of 12fb, 15 and 45 mg/kg, were chosen. DTIC at 60 mg/kgwas used as a positive control. B16-F1 melanoma allograft model onC57BL/6 mice was first chosen for study. After 13 days of treatment(FIG. 24B), compound 12fb inhibited melanoma tumor growth (TGI value) by32% at 15 mg/kg and 82% at 45 mg/kg. Student's t test p value of 12fb at45 mg/kg compared with control was less than 0.001, indicating asignificant difference. The t test p value of 12fb at 15 mg/kg comparedwith control was 0.08, suggesting that this dose was not effective.Comparing 12fb at 45 mg/kg with DTIC at 60 mg/kg, which had a TGI of51%, the t test p value was about 0.001, suggesting that 12fb hadsubstantially better activity than did DTIC. For the control and 12fb 15mg/kg treatment groups, average body weight increased slightlythroughout the experiment period.

To further confirm ABIs' in vivo activity, A375 human melanoma xenograftmodel on SHO mice was used, and 12fb at 25 mg/kg was tested. DTIC at 60mg/kg was used as a positive control again. After 31 days of treatment(FIG. 24C), 12fb inhibited melanoma tumor growth (TGI value) by 69%,whereas DTIC inhibited growth by 52%. The t test p value of 12fbtreatment versus control was less than 0.001, suggesting that 12fbsignificantly inhibited melanoma tumor growth at 25 mg/kg. The t test pvalue of 12fb treatment versus DTIC was less than 0.05, suggesting againthat 12fb had better activity than did DTIC. Average body weight of allgroups increased slightly throughout the experiment period. Physicalactivities for the mice also looked normal, suggesting that 25 mg/kg wasa well tolerated dose for SHO mice.

Example 19 Binding to Colchicine Site Materials and Methods

Each test compound was prepared at 20× concentration in G-PEM buffer(Cytoskeleton Inc., Denver, Colo.) followed by pipetting 10 μL of testcompound into the 96-well plates. Ten microliters of tritiated labeledcolchicine (Perkin-Elmer, Waltham, Mass.) was added to each testingwell. Subsequently, 180 μL bead/tubulin (GE Healthcare Bio-SciencesCorp., Piscataway, N.J.) suspension was added into each well. The platewas incubated for 45 min at 37° C. before it was read by a Topcount NXTplate reader (Perkin-Elmer, Waltham, Mass.). Nonradiolabeled “cold”colchicine was included as a positive control and paclitaxel as anegative control because paclitaxel binds to a different site in tubulinand does not compete for the colchicine site binding. Data wereprocessed using GraphPad Prism software.

Cell Cycle Analysis

Flow cytometry analysis was performed to study cell cycle phasedistribution. A375 cells were cultured in 10-cm tissue culture dishesuntil the confluence was about 80%, and then cells were treated with 0,10, 50, 200, and 1000 nM of colchicine, 12da, 12fb and 12cb, for 24 h ingrowth media. Cellular DNA was stained with PBS containing 50 μg/mLpropidium iodide and 100 μg/mL RNase A. The cell cycle was determinedusing a BD LSR-II cytometer (BD Biosciences, San Jose, Calif.) with10,000 cells scored. Data were analyzed and graphs were prepared usingthe Modfit 2.0 program (Verity Software House, Topsham, Me.).

Results

Three ligand binding sites in tubulin α/β-heterodimer have beenreported: paclitaxel binding site, vinblastine binding site, andcolchicine binding site. The binding affinity of compound 12cb using³H-labeled colchicine and a competitive binding scintillation proximityassay (SPA) was measured. The results confirmed the strong binding of12cb with a binding affinity of 3.4±1.5 μM (FIG. 25A). Colchicine boundtubulin with an IC₅₀ value of 1.8±0.5 μM under these conditions. Theseresults clearly indicated that ABI compounds effectively inhibit tubulinpolymerization.

The binding graph (FIG. 25A) clearly shows that ABIs can competitivelybind to the tubulin colchicine binding site. As the concentration of thethree tested compounds increased from 0.03 μM to 100 μM, increasedtritiated colchicine was competitively stripped away from tubulin andemitted lower SPA counts. The negative control, paclitaxel, gave only aflat line, because theoretically it should not bind to the colchicinebinding site on tubulin. Second, ABIs have relatively high bindingaffinity to the tubulin colchicine binding site. GraphPad Prismcalculated IC₅₀ values for binding showed that 12da has the highestbinding affinity. The binding affinity was positively correlated to invitro antimelanoma activity; the higher the binding affinity, the higherthe antimelanoma activity.

ABIs demonstrated that they arrest cells by cell cycle analysis in theG2/M phase as indication that they target tubulin. Compounds 12da, 12fband 12cb were tested together with colchicine as a positive control onA375 cells (FIG. 25B). Four different concentrations—10, 50, 200, and1000 nM—of each compound were chosen to show the dose effect (FIGS. 25Cand 25D). For controls (no treatment) without interference, about 16% ofA375 cells were distributed in the G2/M phase. For the colchicinetreatment group, as concentration increased from 10 nM to 50 nM, thepercentage of cells distributed in the G2/M phase increased from 14% to85%. ABIs had similar results for A375 cells, in arresting them in theG2/M phase in a dose-dependent manner. The potency of the differentconcentrations in arresting cells in the G2/M phase positivelycorrelated with in vitro activity.

Example 20 In Vitro and In Vivo Pharmacology of Compounds 17ya, 12fa,and 55 Materials and Methods

Cell Culture and Cytotoxicity Assay of Prostate Cancer.

All prostate cancer cell lines (LNCaP, PC-3, and DU145, PPC-1) wereobtained from ATCC (American Type Culture Collection, Manassas, Va.,USA). Human PC-3_TxR, was resistant to paclitaxel and used a MDR modelcompared with PC-3. Cell culture supplies were purchased from CellgroMediatech (Herndon, Va., USA). All cell lines were used to test theantiproliferative activity of compounds 17ya, 12fa, and 55 bysulforhodamine B (SRB) assay. All cancer cell lines were maintained inRPMI 1640 media with 2 mM glutamine and 10% fetal bovine serum (FBS).

In Vitro Microtubule Polymerization Assay.

Porcine brain tubulin (0.4 mg) (Cytoskeleton, Denver, Colo.) was mixedwith 1 and 5 μM of the test compound or vehicle (DMSO) and incubated in100 μL of buffer (80 mM PIPES, 2.0 mM MgCl₂, 0.5 mM EGTA, pH 6.9 and 1mM GTP). The absorbance at 340 nm wavelength was monitored every min for15 min (SYNERGY 4 Microplate Reader, Bio-Tek Instruments, Winooski,Vt.). The spectrophotometer was maintained at 37° C. for tubulinpolymerization.

Metabolic Incubations.

Metabolic stability studies were conducted by incubating 0.5 μM of testcompounds in a total reaction volume of 1 mL containing 1 mg/mLmicrosomal protein in reaction buffer [0.2 M of phosphate buffersolution (pH 7.4), 1.3 mM NADP⁺, 3.3 mM glucose-6-phosphate, and 0.4U/mL glucose-6-phosphate dehydrogenase] at 37° C. in a shaking waterbath. The NADPH regenerating system (solution A and B) was obtained fromBD Biosciences (Bedford, Mass.). For glucuronidation studies, 2 mMUDP-glucuronic acid (Sigma, St. Louis, Mo.) cofactor in deionized waterwas incubated with 8 mM MgCl₂, 25 μg of alamethicin (Sigma, St. Louis,Mo.) in deionized water, and NADPH regenerating solutions (BDBiosciences, Bedford, Mass.) as described previously. The total DMSOconcentration in the reaction solution was approximately 0.5% (v/v).Aliquots (100 μL) from the reaction mixtures used to determine metabolicstability were sampled at 5, 10, 20, 30, 60, and 90 min. Acetonitrile(150 μL) containing 200 nM of the internal standard was added to quenchthe reaction and to precipitate the proteins. Samples were thencentrifuged at 4,000 g for 30 min at RT, and the supernatant wasanalyzed directly by LC-MS/MS.

Analytical Method.

Sample solution (10 μL) was injected into an Agilent series HPLC system(Agilent 1100 Series Agilent 1100 Chemstation, Agilent Technology Co,Ltd). All analytes were separated on a narrow-bore C18 column (AlltechAlltima HP, 2.1×100 mm, 3 μm, Fisher, Fair Lawn, N.J.). Two gradientmodes were used. For metabolic stability studies, gradient mode was usedto achieve the separation of analytes using mixtures of mobile phase A[ACN/H₂O (5%/95%, v/v) containing 0.1% formic acid] and mobile phase B[ACN/H₂O (95%/5%, v/v) containing 0.1% formic acid] at a flow rate of300 μL/min. Mobile phase A was used at 10% from 0 to 1 min followed by alinearly programmed gradient to 100% of mobile phase B within 4 min,100% of mobile phase B was maintained for 0.5 min before a quick ramp to10% mobile phase A. Mobile phase A was continued for another 10 mintowards the end of analysis.

A triple-quadruple mass spectrometer, API Qtrap 4000™ (AppliedBiosystems/MDS SCIEX, Concord, Ontario, Canada), operating with aTurbolonSpray source was used. The spraying needle voltage was set at 5kV for positive mode. Curtain gas was set at 10; Gas 1 and gas 2 wereset 50. Collision-Assisted-Dissociation (CAD) gas at medium and thesource heater probe temperature at 500° C. Multiple reaction monitoring(MRM) mode, scanning m/z 378→210 (17ya), m/z 373→205 (12fa), m/z 410→242(55) and m/z 309→171 (internal standard), was used to obtain the mostsensitive signals. Data acquisition and quantitative processing wereaccomplished using Analyst™ software, Ver. 1.4.1 (Applied Biosystems).

Aqueous Solubility.

The solubility of drugs was determined by Multiscreen Solubility FilterPlate (Millipore Corporate, Billerica, Mass.) coupled with LC-MS/MS.Briefly, 198 μL of phosphate buffered saline (PBS) buffer (pH 7.4) wasloaded into 96-well plate, and 2 μL of 10 mM test compounds (in DMSO)was dispensed and mixed with gentle shaking (200-300 rpm) for 1.5 hoursat RT (N=3). The plate was centrifuged at 800 g for 10 min, and thefiltrate was used to determine its concentration and solubility of testcompound by LC-MS/MS as described previously.

Pharmacokinetic Study.

Male ICR mice (n=3 per group) 6 to 8 weeks of age were purchased fromHarlan Inc., and used to examine the pharmacokinetics (PK) of 17ya,12fa, and 55. All compounds (10 mg/kg) were dissolved in DMSO/PEG300(1/9) and administered by a single intravenously (i.v.) injection (50μL) into the tail vein. Blood samples were collected at 5, 15, and 30min, 1, 1.5, 2, 3, 4, 8, 12, and 24 h after i.v. administration. Micewere given (p.o.) by oral gavage at 20 mg/kg (in Tween80/DMSO/H₂O,2/2/6) of each test compound to evaluate their oral bioavailability.Blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 24 hafter p.o. administration.

Female Sprague-Dawley rats (n=3; 254±4 g) were purchased from HarlanInc. (Indianapolis, Ind.). Rat thoracic jugular vein catheters werepurchased from Braintree Scientific Inc. (Braintree, Mass.). On arrivalat the animal facility, the animals were acclimated for 3 days in atemperature-controlled room (20-22° C.) with a 12 h light/dark cyclebefore any treatment. Compounds 17ya, 12fa, and 55 were administeredi.v. into the thoracic jugular vein at a dose of 5 mg/kg (inDMSO/PEG300, 1/9). An equal volume of heparinized saline was injected toreplace the removed blood, and blood samples (250 μL) were collected viathe jugular vein catheter at 10, 20, 30 min, and 1, 2, 4, 8, 12, 24 h.Rats were given (p.o.) by oral gavage at 10 mg/kg (in Tween80/DMSO/H₂O,2/2/6) of each test compound to evaluate their oral bioavailability. Allblood samples (250 μL) after oral administration were collected via thejugular vein catheter at 30, 60, 90 min, 120 min, 150 min, 180 min, 210min, 240 min, and 8, 12, 24 h. Heparinized syringes and vials wereprepared prior to blood collection. Plasma samples were prepared bycentrifuging the blood samples at 8,000 g for 5 min. All plasma sampleswere stored immediately at −80° C. until analyzed.

Analytes were extracted from 100 μL of plasma with 200 μL ofacetonitrile containing 200 nM the internal standard. The samples werethoroughly mixed, centrifuged, and the organic extract was transferredto autosampler for LC-MS/MS analysis.

PC-3_TxR xenograft studies. PC-3_TxR cells (10×10⁷ per mL) were preparedin RPMI1640 growth media containing 10% FBS, and mixed with Matrigel (BDBiosciences, San Jose, Calif.) at 1:1 ratio. Tumors were established byinjecting 100 μL of the mixture (5×10⁶ cells per animal) subcutaneously(s.c.) into the flank of 6-8-week-old male athymic nude mice. Length andwidth of tumors were measured and the tumor volume (mm³) was calculatedby the formula, π/6×L×W², where length (L) and width (W) were determinedin mm. When the tumor volumes reached 300 mm³, the animals bearingPC-3_TxR tumors were treated with vehicle [Tween80/DMSO/H₂O (2/2/6)], or17ya (10 mg/kg) orally. The dosing schedule was 3 times a week for fourweeks.

Results

17a And 55 Exhibit Broad Cytotoxicity in Cells, IncludingMultidrug-Resistant Cells.

The ability of 17ya and 55 to inhibit the growth of cancer cell lineswas evaluated using SRB assay (Table 15). Both compounds inhibited thegrowth of several human cancer cell lines, including five prostate andone glioma cancer cell lines, with IC₅₀ values in the low nanomolarrange. 17ya exhibited 1.7-4.3 fold higher potency than 55 in these celllines. Paclitaxel-resistant PC-3 (PC-3/TxR) cell line thatover-expresses P-glycoprotein (P-gp), was used to study the effect ofdrug resistance on 17ya and 55 and to compare against its parent, PC-3cell line. The IC₅₀ values of docetaxel were 1.2±0.1 nM and 17.7±0.7 nMin PC-3 and PC-3/TxR cells, respectively. 17ya and 55 were bothequipotent against parent PC-3 and PC-3/TxR, whereas paclitaxel anddocetaxel exhibited relative resistance of 85- and 15-fold,respectively. These data indicate that both 17ya and 55 circumventP-gp-mediated drug resistance.

TABLE 15 Cytotoxicity data of 17ya and 55. Cytotoxicity [IC₅₀ values,mean ± SD nM] 17ya 55 Paclitaxel                                    Cell line                                     Type

PC-3 Prostate 5.2 ± 0.2  16 ± 1.5  0.6 ± 0.05 PC-3/TxR Prostate 2.1 ±0.1 (0.4) 6.7 ± 0.5 (0.4)  51 ± 2.3 (85) LNCaP Prostate  12 ± 0.1  27 ±0.6 1.7 ± 0.2 Du-145 Prostate  17 ± 0.2  38 ± 0.6 5.1 ± 0.1 PPC-1Prostate  21 ± 0.1  36 ± 0.4 2.3 ± 0.8 U87MG Glioma  10 ± 1.6  22 ± 3.0NR IC₅₀ values (mean ± SD) were determined after 96 h treatment (N = 3).Paclitaxel was used as a positive control. Data in parentheses indicatedresistance factor when compared IC₅₀ values in PC-3 and PC-3/TxR. NR,Not Reported.

17ya and 55 Bind to Colchicine-Binding Site on Tubulin, Inhibit TubulinPolymerization, and Induce Cell Apoptosis (FIG. 26).

A competitive mass binding assay was developed to study the interactionof small molecule inhibitors with tubulin. In this study, varyingconcentrations of 17ya or 55 were used to compete withcolchicine-tubulin binding. Both compounds competed effectively withcolchicine for tubulin binding (FIG. 26A); however, their competitivebinding curves deviated substantially from zero at higher concentrationswhen compared to podophylltoxin, a known potent colchicine-site bindingligand. This suggests that both 17ya and 55 exhibited less affinity thanpodophylltoxin or they partially bind to the colchicine-binding site.Vinblastine, the negative control, did not inhibit thecolchicine-tubulin binding, successfully demonstrating the specificityof this competitive mass binding assay

Porcine brain tubulin (>97% pure) was incubated with 17ya or 55 (5 μM)to test their effect on tubulin polymerization (FIG. 26B). 17ya and 55inhibited tubulin polymerization by 47% and 40% at 15 min, respectively.Colchicine at 5 μM was used as a positive control and inhibited tubulinpolymerization by 32%. These data suggest that both 17ya and 55 haveslightly greater inhibition of tubulin polymerization than colchicine.Therefore, the molecular mechanism of these compounds is binding to thecolchicine-binding site, inhibiting tubulin polymerization, and inducingcytotoxicity.

PC-3 and PC-3/TxR cells were exposed to 0.8 to 600 nmol/L of 17ya, 55,or docetaxel for 24 h. The levels of DNA-histone complexes were used torepresent cell apoptosis. Both 17ya and 55 were equally potent to inducecell apoptosis in PC-3 (FIG. 26C) and PC-3/TxR (FIG. 26D) in 24 h.Though, docetaxel was highly potent to induce apoptosis of PC-3 cells,it was weaker in PC-3/TxR cells due to over-expression of P-gp.

17ya and 55 Exhibited Favorable Drug-Like Properties.

Drug-like properties, such as metabolic stability, permeability, aqueoussolubility, and drug-drug interactions, were examined for 17ya and 55(Table 16A). 17ya exhibited greater metabolic stability, and aqueoussolubility than 55. Both chemicals exhibited more than adequatepermeability values, suggesting their potential to be orally used. Inaddition, both 17ya and 55 showed high IC₅₀ values in micromolar rangeon CYP enzyme inhibition assays, indicating that both compounds mayavoid drug-drug interactions through main CYP liver enzymes. Overall,both compounds exhibited favorable drug-like properties.

TABLE 16A Drug-like properties of compound 17a and 55. Metabolicstability, permeability, solubility, and potential drug-druginteractions were evaluated. Each value represents the mean fromduplicate studies. positive controls Measurment Units 17ya 55 (mean)Metabolic stability half-life in human liver min >60 28 Verapamilmicrosomes (12)   Permeability P_(app(A→B)) in CaCO-2 assay 10⁻⁶ cm/s 3699 Propranolol (19)   Aqueous solubility μg/mL >75 19 1 h (1.1)Drug-drug interactions IC₅₀ value in Cyp3A4 μM 20 5.5 Ketoconazole(substrate: Testosterone)  (0.02) IC₅₀ value in Cyp2D6 μM >50 34Quinindine (substrate: Dextromethorphan) (0.1) IC₅₀ value in Cyp2C19 μM6.6 5.3 Ticlopidine (substrate: (S)-mephenytoin)  (0.37) IC₅₀ value inCyp2C9 μM 17 4.9 Sulfaphenazole (substrate: Diclofenac) (0.5) IC₅₀ valuein Cyp1A2 μM 9.2 8.1 Furafylline (substrate: Phenacetin) (2.2)

TABLE 16B Summary of drug-like and pharmacokinetic properties of 17ya,12fa, 55, and 1h. 17ya 12fa 55 1h

Molecular weight 377  372 409 355 IC₅₀ in PC3 (nM) nM  10  35  28  21Half-life in HLM (Phase I) min ~80  44  30  17 Half-life in HLM (PhaseI + II) min ~90 NA  43  17 Solubility μg/mL >75  12  19  1RatPK_IV5mgk_Cl mL/min/kg  16 7.7 (2.5 mpk) RatPK_IV5mgk_V L/kg    1.94.9 (2.5 mpk) RatPK_PO10mgk_Cmax ng/mL 1109 212 RatPK_PO10mgk_AUC min *μg/mL  218  37 RatPK_Bioavailability % F  35    3.3 MousePK_IV10mgk_ClmL/min/kg  61 130 MousePK_IV10mgk_V L/kg   4    4.9 MousePK_PO20mgk_Cmaxng/mL 2592 NA MousePK_PO20mgk_AUC min * μg/mL  201 NAMousePK_Bioavailability % F  62 NA

As shown in Table 16B, 17ya had a half-life of 80 min by phase Ireaction, suggesting that 17ya was stable in phase I metabolicprocesses. The half-life (90 min) in the presence of UDP-glucuronic acidwas similar to that observed in its absence. These data suggested that17ya is stable in human liver microsomes, and it was hoped that lowclearance and long half-life will be obtained in human. On the otherhand, 55 exhibited 30 and 43 min as half lives when it was in thepresence and absence of UDP-glucuronic acid, respectively. Compound 12fashows the half-life with 44 in phase I. These data suggested that allthree compounds showed acceptable stability in human liver microsomes,and 17ya is more stable than 12fa and 55. When investigating theirmetabolism, it was found that 12fa and 55 exhibited higher levels ofketone-reduction (data not shown), suggesting that 12fa and 55 are morelabile than 17ya.

Compound 17ya Exhibited Great Aqueous Solubility, 12fa and 55 ShowedAcceptable Solubility.

Compound 17ya contained an imidazole ring, and this ring improvedaqueous solubility, resulting in >75 μg/mL aqueous solubility (Table16A). Compounds 12fa and 55 exhibited less aqueous solubility, andexhibited 12 and 19 μg/mL, respectively. Overall, 17ya demonstrated agreat aqueous solubility, and 12fa and 55 showed acceptable aqueoussolubility, and much improved over 1h. The greater solubility of 12fatranslated into much improved oral bioavailability compared to 1h (35%vs. 3.3% in rat). Similarly for 17ya and 55, aqueous solubilitycorrelated with much improved oral bioavailability as discussed infra(Table 17).

Pharmacokinetic Studies of 17ya and 55 in Mice, Rats and Dogs.

The pharmacokinetic parameters of 17ya and 55 given in a single (i.v. orp.o.) dose in ICR mice, Sprague-Dawley rats, and beagle dogs aresummarized in Table 17. 17ya exhibited low clearance in mice and rats,suggesting that 17ya exhibited metabolic stability, and minimalfirst-pass metabolism in these species. In addition, 17ya had moderatevolume of distribution in mice and rats, indicating that it may properlydistribute into tissues, including tumors. Unlike in mice and rats,surprisingly, the total clearance of 17ya in dogs was high. Two abundantmetabolites in dog plasma, a hydroxylated metabolite and an unknownmetabolite with +34 m/z of the parent (data not shown), were consistentwith those found in dog liver microsomes. In summary, higher clearanceand lower oral exposure was obtained for 17ya compared to 55 in dogs,but not in mice and rats. In addition, 17ya exhibited abundantmetabolites only in dog liver microsomes, but not in mouse, rat or humanliver microsomes (data not shown). 17ya showed acceptable 21%, 36%, and50% oral bioavailability in rats, mice, and dogs, respectively.Meanwhile, 55 had low clearance in rats, and moderate clearance in miceand dogs. Similar to 17ya, 55 exhibited moderate volume of distributionin these species. 55 had constant oral bioavailability rates among threespecies (24%-36%). These properties indicate that both 17ya and 55 arepotential orally available tubulin inhibitors.

TABLE 17 Pharmacokinetic studies of compounds 17ya and 55 in mice, rats,and dogs. 17ya 55 IV PO IV PO Mouse PK (N = 3) Dose, mg/kg 10 20 10 20Clearance, 19 NR 40 NR mL/min/kg Vss, L/kg 2.9 NR 1.3 NR t_(1/2), min101 339 46 126 AUC, 540 384 249 171 min * μg/mL C_(max), ng/mL 4800 15607739 1253 F, % 36% 34% Rat PK (N = 3) Dose, mg/kg 5 10 5 10 Clearance,9.5 ± 2.3 NR 10 ± 1.4 NR mL/min/kg Vss, L/kg 1.8 ± 0.2 NR 1.0 ± 0.1 NRt_(1/2), min 139 ± 24  206 ± 12   73 ± 5.0 350 ± 214 AUC, 553 ± 143 233± 134 509 ± 73  246 ± 163 min * μg/mL C_(max), ng/mL 3672 ± 519  999 ±445 4609 ± 55  757 ± 520 F, % 21% 24% Dog PK (N = 4) Dose, mg/kg 2 5 2 5Clearance, 109 ± 29  NR  15 ± 3.2 NR mL/min/kg Vss, L/kg 94 ± 95 NR 0.9± 0.2 NR t_(1/2), min 2757 ± 1573 1695 ± 439  82 ± 15 191 ± 9.0  AUC,18.5 ± 4.7  23.1 ± 11.3 141 ± 30  128 ± 154 min * μg/mL C_(max), ng/mL400 ± 118 210 ± 133 2552 ± 576   862 ± 1010 F, % 50% 36%

17ya and 55 Inhibit Paclitaxel Resistant Prostate (PC-3/TxR) XenograftsGrowth.

PC-3 (FIG. 27A) and paclitaxel-resistant prostate cancer (PC-3/TxR)(FIG. 27B) cells were inoculated in nude mice and the tumor volumes wereallowed to reach about 150-300 mm³. Docetaxel (10 or 20 mg/kg), which isin clinic for prostate cancer, was used to evaluate its effectiveness inmodels of P-gp-mediated drug resistance in vivo. PC-3/TxR tumor wasfound to be fast-growing and the volume reached 1500-2500 mm³ at thetermination of the study. Though 10 and 20 mg/kg intravenouslyadministered docetaxel exhibited a dose response in both models (FIGS.27A and 27B), the tumor growth inhibition (TGI) effect decreased from84% TGI in PC-3 tumors to 14% TGI in PC-3/TxR tumors when intravenouslydosed at 10 mg/kg (Table 18). In addition, at the higher dose (20mg/kg), docetaxel elicited partial regression (>100% TGI) of PC-3tumors, but barely 56% TGI in PC-3/TxR tumors. The effectiveness ofdocetaxel in PC-3/TxR tumors was dramatically decreased when compared tothat in PC-3 tumors, suggesting that the efficacy was impaired byP-gp-mediated drug resistance, and these results are in very goodagreement with our in vitro cytotoxicity or apoptosis data. In contrastto the lack of efficacy of docetaxel in PC-3/TxR tumors, orallyadministered 17ya (6.7 mg/kg) demonstrated more than 100% TGI without aneffect on their body weights (FIG. 27B and Table 18). In addition, 2 outof 4 nude mice bearing PC-3/TxR tumors were tumor free on day 19 (datanot shown).

The PC-3/TxR xenograft model was further utilized to evaluate efficaciesof 17ya (in other dosing schedules) and 55. The maximal tolerated dose(body weight loss>20%) of 17ya was found to be 10 mg/kg, when orallydosed once daily for four days; or at 3.3 mg/kg twice a day (b.i.d.) forfive days (data not shown). As shown in FIG. 27C, 3.3 mg/kg of 17ya wasdosed b.i.d. for first consecutive four days in the first week, and theschedule was then changed to once daily between weeks 2 and 4. Theresult shows that partial regression was obtained during day 4-19, andthe TGI was 97%, and one of the seven mice was tumor free on day 26.Higher dose (10 mg/kg) with lower dosing frequency (q2d) of 17ya (FIG.27D) elicited partial regression during days 13 to 29. These datasuggest that regimens with optimized doses and dosing schedules willfacilitate 17ya to successfully inhibit PC-3/TxR tumors. 55, was orallyadministered to nude mice with 10 or 30 mg/kg b.i.d., and five times aweek between weeks 1 and 4. As shown in FIG. 27C, the inhibitionprofiles exhibit a dose-response in PC-3/TxR tumor. The TGI value was59% for the treatment group with a lower dose (10 mg/kg). Moreover, thehigher dose (30 mg/kg) started to show partial regression (>100% TGI)from day 19 to the termination of the study (day 26). Some mice in thevehicle group lost body weight at the endpoint, in part, due to cancercachexia. On the contrary, mice treated with 17ya (3.3 mg/kg) or 55 (30mg/kg) were gaining weight (Table 18), suggesting that these optimizeddoses of 17ya or 55 may be well-tolerated and were preventive of cancercachexia.

TABLE 18 Antitumor activity of compounds 17ya and 55 versusconcomitantly evaluated docetaxel in vivo. Dosing End Number Body weight(g) Tumor size (mm³) Schedule point End/Start Start End Start End TGI(%) PC-3 xenograft Vehicle_IV day 1and 9 day 19 6/6 30 ± 2 32 ± 4 271 ±83 875 ± 292 — Docetaxel_IV_10mpk day 1and 9 day 19 5/5 29 ± 2 24 ± 2247 ± 49 341 ± 101 84 Docetaxel_IV_20mpk day 1and 9 day 19 5/5 28 ± 3 24± 3 243 ± 68 172 ± 62  >100 PC-3/TxR xenograft Vehicle_IV day 1and 9 day19 5/5 33 ± 1 26 ± 5 171 ± 57 2061 ± 858  — Docetaxel_IV_10mpk day 1and9 day 19 4/4 31 ± 2 25 ± 2 143 ± 20 1774 ± 183  14 Docetaxel_IV_20mpkday 1and 9 day 19 4/4 30 ± 1 25 ± 4 170 ± 86 999 ± 905 56 17ya_PO_6.7mpkqd x 5/w day 19 4/4 33 ± 3 34 ± 3 172 ± 69 126 ± 100 >100 Vehicle_POb.i.d x 5/w day 26 6/7 30 ± 2 25 ± 2 156 ± 30 2591 ± 1423 — 55_PO_10mpkb.i.d x 5/w day 26 7/7 29 ± 2 26 ± 3 143 ± 44 1152 ± 433  59 55_PO_30mpkb.i.d x 5/w day 26 7/7 29 ± 3 30 ± 2 134 ± 34 101 ± 19  >10017ya_PO_3.3mpk^(a) qd x 5/w day 26 7/7 29 ± 2 30 ± 2 139 ± 44 214 ± 17297 Vehicle_PO q2d x 3/w day 29 5/5 24 ± 2 21 ± 1 299 ± 40 1521 ± 580  —17ya_PO_10mpk q2d x 3/w day 29 5/5 24 ± 2 28 ± 2  294 ± 156 237 ±103 >100 Dosing schedule: qd x 5/w = one administration given on fiveconsecutive days per week; b.i.d. x 5/w = two administrations given onfive consecutive days per week; or q2d x 3/w = every other dayadministration or three times a week. ^(a)Dose schedule was twoadministrations given on four consecutive days of the first week, anddose schedule was changed (because of toxicity) to one administrationgiven on five consecutive days per week for the second to fourth week.

Brain Penetration of 17ya and 55 in Nude Mice.

Whole brain concentrations in nude mice at 1 h and 4 h after oraladministration of 20 mg/kg 17ya or 55 were determined (Table 19). Theratios of brain to plasma concentrations were determined and compared todocetaxel in the nude mice. 55 exhibited greater brain penetration than17ya and docetaxel. 17ya only exhibited slightly greater brain/plasmaconcentration ratios than docetaxel at both 1 and 4 h. The brainconcentrations of 55 reached 14 to 19% of plasma concentrations at 1 hand 4 h, respectively, showing a 3.2-fold higher brain/plasma ratio atboth 1 h and 4 h compared to docetaxel. These data suggest that 55exhibited potentially favorable properties to treat glioma, since it hasgreater brain penetration and high potency (22 nM, Table 15) in gliomacells.

TABLE 19 Brain-Blood Barrier (BBB) studies of compounds 17ya and 55.Brain and plasma concentrations were determined in nude mice at 1 and 4h after administration of docetaxel (IP, 10 mpk), 17ya (PO, 20 mpk), and55 (PO, 20 mpk). Each value represents the mean ± SD from 3 nude mice.Docetaxel 17ya 55 Measurment 1 hr 4 hr 1 hr 4 hr 1 hr 4 hr Brain (ng/mL)33 ± 14 20 ± 9 124 ± 108 49 ± 32 180 ± 44 73 ± 18 Plasma (ng/mL) 768 ±92  345 ± 94 2058 ± 1252 570 ± 438 1669 ± 867 380 ± 32  Brain/plasma (%)4.4 ± 2.0  6.0 ± 2.9 5.4 ± 1.9 8.9 ± 1.7   14 ± 7.9  19 ± 3.1

Example 21 Pharmacokinetics of Compounds of this Invention

TABLE 20 Half life in Half life in Half life in Half life in Half lifein Monkey Human liver Mouse liver Rat liver Dog liver liver microsomemicrosome microsome microsome microsome Compound ID (min) (min) (min)(min) (min) 1h 17 <5 31 19 <5 2e-cis 35 2i 32 2k 10 9 32 16 <5 2l 20 1149 30 8 6a 32 3.43 12 13 16 6b 40 10 9 30 13 6c 47 13 14 29 9 7d 24 3742 29 15 12da 23 8 28 17 12fa 56 23 46 26 12fb 37 12dab 21 <5 12 46

Example 22 Biological Activity of 4-Substituted Methoxybenzoyl-ArylThiazole (SMART) Compounds 1h, 2k, and 2l: Active Microtubule InhibitorsMaterials and Methods

In vitro microtubule polymerization assay. Bovine brain tubulin (0.4 mg)(Cytoskeleton, Denver, Colo.) was mixed with 10 μM of the test compoundor vehicle (DMSO) and incubated in 100 μl of buffer (80 mM PIPES, 2.0 mMMgCl₂, 0.5 mM EGTA, pH 6.9 and 1 mM GTP). The absorbance at 340 nmwavelength was monitored every min for 15 min (SYNERGY 4 MicroplateReader, Bio-Tek Instruments, Winooski, Vt.). The spectrophotometer wasmaintained at 37° C. for tubulin polymerization.

MS Competition Binding Assay.

Colchicine, vinblastine, and paclitaxel (1.2 μM for each) were incubatedwith tubulin (1.2 mg/mL) in the incubation buffer (80 mM PIPES, 2.0 mMMgCl₂, 0.5 mM EGTA, pH 6.9) at 37° C. for 1 hr. 1h (0.5-125 μM) wasexamined to individually compete with colchicine-, vinblastine-, andpaclitaxel-tubulin binding. The free-form ligands were separated fromtubulin or microtubule using an ultrafiltration method(microconcentrator) (Microcon, Bedford, Mass.) with a molecular cutoffsize of 30k Da. Colchicine, vinblastine and paclitaxel were determinedby LCMS/MS method. The ability of 1h to inhibit the binding of ligandswas expressed as a percentage of control binding in the absence of anycompetitor. Each reaction was run in triplicate.

Cell Culture and Cytotoxicity Assay of Prostate and Melanoma Cancer.

All prostate and melanoma cell lines were obtained from ATCC (AmericanType Culture Collection, Manassas, Va., USA), while cell culturesupplies were purchased from Cellgro Mediatech (Herndon, Va., USA). Theantiproliferative activity of the compounds was examined in four humanprostate cancer cell lines (LNCaP, DU 145, PC-3, and PPC-1) and twohuman melanoma cell lines (A375 and WM-164). Human ovarian cell lineOVCAR-8 and its resistant cell line that over-expresses P-gp,NCI/ADR-RES, were used as MDR models. Both ovarian cell lines wereobtained from National Cancer Institutes (NCI). All prostate cancer celllines were cultured with 10% fetal bovine serum (FBS).

Cell Cycle Analysis.

Flow cytometry was performed to study the effects of the compounds oncell cycle distribution. PC-3 and A375 cells were treated in growthmedia with the indicated concentrations of compounds 1h, 2k, 2l for 24h. Cellular DNA was stained with 100 μg/mL propidium iodide and 100μg/mL RNase A in PBS and flow cytometry was performed to determine thecell cycle distribution of the cells.

Apoptosis Detection by ELISA.

Quantification of the enrichment of mono- and oligonucleosomes in thecytoplasm was used to determine the ability of the compounds to induceapoptosis (cell death detection ELISA PLUS, Roche, Germany) followingthe manufacturer's instructions.

Pharmacokinetic Study.

Male ICR mice (n=3 or 4 per group) 6 to 8 weeks of age were purchasedfrom Harlan Inc., and used to examine the pharmacokinetics (PK) of thecompounds. 1h, 2k, 2l (15 mg/kg) were dissolved in PEG300/DMSO (1/4) andadministered by a single i.v. injection into the tail vein. Bloodsamples were collected at 2, 5, 15, and 30 min, 1, 2, 4, 8, 16, and 24hr after administration. Male Sprague-Dawley rats (n=4; 254±4 g) werepurchased from Harlan Inc. (Indianapolis, Ind.). 1h, 2k, wereadministered intravenously into the jugular venous catheters at 2.5mg/kg (in DMSO/PEG300, 1/4). Blood samples (250 μL) were collected at10, 20, 30 min, and 1, 2, 4, 8, 12, 24, 48 h. A protein precipitationmethod was used for sample preparation. An aliquot (200 μL) ofacetonitrile (ACN) was added to 100 μL of plasma and then was thoroughlyvortexed for 15 s. After centrifugation, the supernatant was analyzed byliquid chromatography tandem mass spectrometry (LC-MS/MS). The PKparameters were determined using Non compartment analysis (WinNonlin,Pharsight Corporation, Mountain View, Calif.).

PC-3 and A375 tumor xenograft studies. PC-3 and A375 cells (5×10⁷ permL) were prepared in phenol red-free growth media containing 10% FBS,and mixed with Matrigel (BD Biosciences, San Jose, Calif.) at 1:1 ratio.Tumors were established by injecting 100 μL of the mixture (2.5×10⁶cells per animal) subcutaneously (s.c.) into the flank of 6-8-week-oldmale athymic nude mice. Length and width of tumors were measured and thetumor volume (mm³) was calculated by the formula, π/6×L×W², where length(L) and width (W) were determined in mm. When the tumor volumes reached150 mm³, the animals bearing PC-3 tumors were treated with vehicle[Captex200/Tween80 (1/4)], 1h (5 and 15 mg/kg), 2k (5 and 15 mg/kg) and2l (50 mg/kg) intraperitorally for 21 days. Vinblastine (0.5 mg/kg) wasused as the positive control and dosed q2d with vehicle [DMSO/PEG300(1/9)]. On the other hand, A375 tumor bearing mice were treated for 34days with vehicle [Captex200/Tween80 (1/4)], 1h (20 mg/kg) or 2k (15mg/kg). Doses were selected based on acute toxicity studies of 1h and 2kin ICR mice (n=2/group) showing that doses up to 30 mg/kg and 15 mg/kg,respectively, did not cause greater than 10% loss of body weight after 4consecutive days of intraperitoneal dosing.

In Vivo Antitumor Activity [Tumor Growth Inhibition (% T/C), TumorGrowth Delay (T-C Value), and Tumor Cell Kill (Total Log Cell Kill)].

Evidence of drug effect is described by the following parameters: %T/C=[Δ tumor volume of treated group]/[Δ tumor volume of controlgroup]×100%. The T-C values (tumor growth delay) were based on themedian time (in days), required for the treatment (T) and the controlgroup (C) tumors, to reach a predetermined size (600 mm³ in this study).These values were then used for the quantitation of the tumor cell killfollowing the equation: log cell kill=(T-C)/(3.32×Td). Td is the tumorvolume-doubling time in days. In this study, we defined the doublingtime required for the tumor to increase from 300 to 600 mm³.

Rotarod Test.

ICR mice received training three times a day for two days to enable themto stay on the rotating rod for >120 seconds at 12 rpm. Mice were thenrandomized by the length of time that they could stay on the rotatingrod and divided into 7-8 mice per group. 1h at a dose of 5 or 15 mg/kgin Captex200/Tween80 (1/4) was administered by intraperitonealinjection. Vinblastine at a dose of 0.5 mg/kg/day was used as a positivecontrol under the same conditions. The rotarod test was performed twicea week. Treatment was stopped on day 31, and post observation wasexamined on weeks 1, 2, and 4 after termination of the treatment. Therod speed was increased from 59 rpm to 40 rpm over a period of 5 min.Performance was measured as the length of time that a mouse could stayon the rotating rod.

In Vivo Drug Resistance Studies.

At the end of the PC-3 xenograft studies, solid tumors from control and1h treated (15 mg/kg) groups were removed and digested with 0.1%collagenase (Type I) and 50 mg/mL DNAse (Worthington Biochemical Corp.,Freehold, N.J.). Dispersed cells were plated in RPMI medium+10% FBS andincubated at 37° C. and 5% CO₂ for 24 hr to allow attachment. Theantiproliferative effects of 1h were compared to determine whether tumorcells remaining in PC-3 xenografts retained sensitivity to drug. ThePC-3 cells obtained from ATCC were used as in vitro control. Statisticalanalyses were performed using simple t-Test.

Results

Based on structure-activity relationship studies, three compounds (FIG.28A) were selected for biological characterization. While 1h and 2k arehighly potent molecules with low nanomolar cytotoxic properties, 2l,which was rationally designed as a potential metabolite with improvedsolubility, had the least potent antiproliferative effects (Table 21).

TABLE 21 In vitro efficacy of compounds on prostate, melanoma and drugresistant cell lines (n = 3, mean ± SE). Paciltaxel, vinblastine, andcolchicine were used as positive controls as previously reported. IC₅₀ ±SEM (nM) Cell line Cell type SMART-H SMART-F SMART-OH PaclitaxelVinblastine Colchicine LNCaP Prostate 28 ± 4^(a) 6 ± 1^(a) 103 ± 9  1.7± 0.2 1.1 ± 0.1 16 ± 4 PC-3 Prostate 21 ± 1^(a) 13 ± 1^(a)  87 ± 5 4.8 ±0.3 2.1 ± 0.2 11 ± 1 Du-145 Prostate 71 ± 4^(a) 12 ± 1^(a)  116 ± 14 5.1± 0.1 1.8 ± 1.1 10 ± 2 PPC-1 Prostate 43 ± 5^(a) 8 ± 1^(a) 76 ± 2 2.3 ±0.8 1.1 ± 0.4 20 ± 1 B16-F1 Melanoma 55 ± 5^(a) 43 ± 21^(a) 113 ± 6  17± 2  4.7 ± 0.7 29 ± 5 A375 Melanoma 28 ± 5^(a) 33 ± 14^(a)  93 ± 11 12 ±3  1.1 ± 0.2 20 ± 3 OVCAR-8 Ovarian 35 ± 2  34 ± 3   110 ± 8  4.7 ± 0.13.9 ± 0.1 17 ± 1 NCI/ADR-RES Ovarian 13 ± 1  12 ± 1   45 ± 5 6263 ± 634 582 ± 57  1113 ± 79  Resistance 0.4 0.4 0.4 1333 149 65 Factor SMART-Hin Table 21 is 1h; SMART-F in Table 21 is 2k; and SMART-OH in Table 21is 2l.

SMARTs Inhibit Microtubule Polymerization by Binding to the ColchicineBinding Site on Tubulin.

Bovine brain tubulin (>97% pure) was incubated with the individualcompounds (10 μM) to test their effect on tubulin polymerization (FIG.28B). While 1h and 2k inhibited tubulin polymerization by 90%, 2linhibited the polymerization by only 55%. Previous studies demonstrateda concentration-dependent inhibition of tubulin polymerization by 1h. Inaddition, under the same experimental conditions, the IC₅₀ for 1h (4.23μM) is similar to that of colchicine (4.91 μM). These data suggest thatthe compounds exhibit strong antitubulin polymerization activity thatcorresponds well with their cytotoxicity (Table 21). The ability of thecompounds to compete for known binding sites on tubulin was determinedusing a novel MS competitive binding assay, which was developed in ourlaboratory. Three tubulin ligands, corresponding to the three bindingsites on tubulin, colchicine, vinblastine, and paclitaxel were used forthese competitive binding studies. It was found that, over aconcentration range of 0.1-125 μM, 1h specifically competed withcolchicine binding to tubulin, but it did not compete with eithervinblastine or paclitaxel binding to tubulin (FIG. 28C).

SMART Compounds Inhibit the Growth of Multidrug-Resistant Cancer CellLines.

The ability of the compounds to inhibit the growth of cancer cell lineswas evaluated using the SRB assay. As shown in Table 21, the compoundsinhibited the growth of several human cancer cell lines, including fourprostate cancer cell lines, and two melanoma cell lines, with IC₅₀values in the low nanomolar range. Out of the three compounds, 2l wasthe least potent (IC₅₀ 76-116 nM). 2k exhibited the bestantiproliferative effect with IC₅₀ values between 6 and 43 nM inprostate cancer and melanoma cell lines. In addition, the effect of thecompounds in the OVCAR-8 and NCI/ADR-RES cell lines was also evaluated(Table 21). The compounds were equally potent against MDR cell(NCI-ADR-RES) and the parent cell line (OVCAR-8). Paclitaxel,vinblastine, and colchicine exhibited relative resistance values of1333, 149, and 65 times, respectively (Table 21). These data indicatethat the compounds circumvent P-gp-mediated drug resistance.

SMART Compounds Arrest PC-3 (Prostate) and A375 (Melanoma) Cells inG2/1M Phase of Cell Cycle and Induce Cell Apoptosis.

PC-3 and A375 cells were exposed to 10, 50, 200, and 1000 nM of thecompounds for 24 h. Treatment with the SMART compounds resulted inconcentration-dependent accumulation of both PC-3 and A375 cells in theG2/M phase with concomitant decreases in the percentage of cells inG0/G1 phase (FIGS. 29A and 29B). The proportion of cells in G2/M phasesignificantly increased when treated with 50 to 200 nM of 1h, 2k, 2l.Apoptosis was then examined by measuring the level of cytoplasmicDNA-histone complexes in PC-3 and A375 cells after 24 h treatment.Increasing concentration of the SMART compounds increased the level ofcytoplasmic DNA-histone complexes in PC-3 and A375 cells (FIG. 29C). Theeffect was more pronounced in A375 cells than PC-3 cells, but apoptosiswas evident in both cell types. 1h and 2k induced moderate apoptosis ata concentration of 50 nM, while 2l induced apoptosis only atconcentrations greater than or equal to 200 nM.

In Vivo PK Profile of SMART Compounds.

A single dose bolus of each compound (15 mg/kg) was administered by tailvein injection to ICR mice to characterize their pharmacokinetics (FIG.30A). 1h and 2k exhibited similar PK properties, but 2l exhibitedslightly greater AUC than 1h and 2k indicative of a lower clearance for2l (Table 22). 2l also had 2-3 times higher V_(ss) than that of 1h and2k. The clearance values for all three compounds were equal to or higherthan 90 mL/min/kg, the hepatic blood flow rate in mice, suggesting thatin addition to hepatic removal, other degradation routes may be involvedin the elimination of the compounds. The pharmacokinetics of 1h and 2k(2.5 mg/kg) were also examined in rats (FIG. 30B). Interestingly, lowclearance values and hepatic extraction rates were obtained by bothcompounds, suggesting that these compounds exhibit species differencesin clearance. In rats, 1h exhibited favorable pharmacokineticproperties, which are low clearance (6 mL/min/kg), moderate volume ofdistribution (7.6 L/kg), long half-life (24 hr), and high exposure (AUC,5.8 hr*μg/mL) (Table 22) when administered iv.

TABLE 22 Pharmacokinetic parameters of SMART compounds. SMARTs wereadministrated 15 mg/kg and 2.5 mg/kg i.v. in mice and rats,respectively. In vivo, pharmacokinetic parameters of SMART compoundsSMART- Species Parameter Unit SMART-H SMART-F OH Mice AUC hr * μg/mL 1.92.2 2.6 t_(1/2) min 140 141 740 V_(ss) L/kg 4.9 6.6 16.5 CL mL/min/kg130 112 90 Rats AUC hr * μg/mL 5.8 1.6 NA t_(1/2) min 1431 2410 NAV_(ss) L/kg 7.6 34 NA CL mL/min/kg 6 11 NA NA, not available SMART-H inTable 22 is 1h; SMART-F in Table 22 is 2k; and SMART-OH in Table 22 is2l.

SMART Compounds Inhibit Prostate and Melanoma Xenografts Growth WithoutNeurotoxicity.

Prostate cancer PC-3 and melanoma A375 tumors in mice were allowed toreach a volume of 150 mm³ and then tumor-bearing mice were treated withthe SMART compounds. As shown in FIG. 31A, tumor volumes in the controlgroup increased to 680 mm³ over the 21 day duration of the study. Tumorvolumes in the 1h treated group increased to 370 mm³ (5 mg/kg treatment)and 176 mm³ (15 mg/kg treatment) by day 21, indicating strong anti-tumoractivity for this compound. Tumors in the 2k-treated animals increasedto 269 mm³ (5 mg/kg treatment) and 292 mm³ (15 mg/kg treatment), whileanimals in the 2l (50 mg/kg) treated group had tumors of 331 mm³ at day21. This reduction in tumor volume reversed upon withdrawal of SMARTcompounds (data not shown). Table 23 summarized the in vivo efficacy (%T/C, T-C values, and log cell kill) of SMART compounds.

TABLE 23 In vivo efficacy of SMART compounds (administered i.p.) onprostate (PC-3), melanoma (A375). % T/C, T-C value, and log cell killare summarized. The doubling time of melanoma xenograft was 4.6 d.Vinblastine was used as the positive control. % T/C ≦ 42% is consideredto be moderately active by National Cancer Institute criteria. NA, notavailable. Median time Total Dosage Xenograft % to reach T-C logCompound (mg/kg) model T/C 600 mm³ (days) cell kill Vehicle NA Prostate100 19 days NA NA Vinblastine 0.5 Prostate 29 NA NA NA SMART-H 5Prostate 29 NA NA NA SMART-H 15 Prostate 4 NA NA NA SMART-F 5 Prostate21 NA NA NA SMART-F 15 Prostate 24 NA NA NA SMART-OH 50 Prostate 34 NANA NA Vehicle NA Melanoma 100 18 days NA NA SMART-H 20 Melanoma 30 28days 10 0.7 SMART-F 15 Melanoma 28 29 days 11 0.7 SMART-H in Table 23 is1h; SMART-F in Table 23 is 2k; and SMART-OH in Table 23 is 2l.

1h tumor elicited % T/C=29% and 4% at 5 and 15 mg/kg treatment (alldoses were intraperitoneal (i.p.)), respectively, whereas, 2k elicited %T/C of 21% and 24% at 5 and 15 mg/kg treatment, respectively. The highdose of 2l (50 mg/kg) exhibited the % T/C of 34%. Vinblastine, thepositive control, showed % T/C of 29% at day 22 in PC-3 xenografts (FIG.31B). Body weight measurements, to monitor toxicity, indicated that only1 of 8 mice treated with 1h (15 mg/kg), and 2 out of 7 mice treated with2k (15 mg/kg) lost more than 15% body weight. In addition to theantitumor effects of the compounds on PC-3 prostate tumors, 1h (20mg/kg) and 2k (15 mg/kg) demonstrated a significant reduction of A375tumors. As shown in FIG. 31C, the tumor volumes of control groupincreased to 2183 mm³, whereas the 14 volumes in 1h and 2k treatmentgroups increased to 775 mm³ and 722 mm³, respectively. 1h and 2ktreatment evoked % T/C of 28% and 29%, respectively. Rotarod tests wereperformed to examine the in vivo neurotoxic effects of 1h. Based on theresult of in vivo efficacy experiments, 5 or 15 mg/kg [i.p.administration, Captex200/Tween80 (1/4)] of 1h was chosen to study theeffect on motor coordination. A 0.5 mg/kg treatment with vinblastine wasused as the positive control under the same conditions. As shown in FIG.31D, vinblastine gradually reduced the time (in seconds) that the micecould stay on the rotating rod, and attained significance by days 27 and31 (p<0.05) compared to the vehicle group. However, no significantdifference was observed in the 1h treatment groups, suggesting that 1hdid not cause neurotoxicity in ICR mice at doses that are associatedwith antitumor effects.

1h Did not Develop Drug-Resistance in PC-3 Tumor Bearing Mice.

We excised the PC-3 tumors from nude mice after 21 days of treatmentwith vehicle (n=3) or 15 mg/kg 1h (n=3). Solid tumors were digested anddispersed into cells as described in the methods section. PC-3 cell linefrom ATCC (American Type Culture Collection, Manassas, Va., USA) wasused as a control. IC₅₀ values were 29.1±1.1, 29.1±0.8, and 30.4±0.5 nMin PC-3 cells from ATCC, and dissociated cells from vehicle and 1htreated tumors, respectively. These data demonstrate that 1h did notinduce drug-resistance in PC-3 tumors after 21 days of continuous 1htreatment.

Example 23 Molecular Modeling Methods

All molecular modeling studies were performed with Schrödinger MolecularModeling Suite 2008 (Schrödinger LLC, New York, N.Y.), running on a DellLinux workstation. Because the size of ABI compounds are much closer tothat of ABT-751, rather than DAMA-colchichine, we selected tubulincomplex with ABT-751 (PDB code: 3 KHC) as our modeling system. ABIs werebuilt and prepared using the Ligprep module, and they were docked intothe ABT-751 site using the Glide module in Schrödinger Suite. The bestdocking complexes were subject to restricted molecular dynamics torelease any strains using Macromodel module with OPLS-2005 forcefield.The ligand and its surrounding residues within 15 Å were allowed to movefreely, while residues outside the 15 Å radius were kept rigid.

Results

Molecular modeling for binding ABI compounds in tubulin was studied.Several crystal structures of the ligand-tubulin complex are availablein the PDB databank, with the most recent one from Dorleans et al. Ingeneral, the colchicine binding pocket tolerates a variety of molecularstructures, which may indicate substantial conformation changes uponligand binding. In fact, Dorleans et al. solved the crystal structuresof both the empty tubulin dimer and the ligand-tubulin complex. Theyfound that, without the presence of ligand, loop 7 (T7, residues244-251, FIG. 32) in the beta-monomer folds in to occupy the bindingpocket, while it flips out upon ligand binding. The associated helix 7(H7, residues 224-243) and helix 8 (H8, residues 252-260) were displacedupon ligand binding. It is conceivable that the extent to which T7 isdisplaced depends on the size of individual ligand. This flexibilitypresents a significant challenge to understand the precise binding modesfor individual ligands without solving actual crystal structures.Nevertheless, careful analysis of the possible binding modes couldprovide some insights into the binding of different ligands.

The binding modes of 12cb and 11cb (stick model) are shown in FIGS. 32Aand 32B. For comparison, the crystal structure complexes of ABT-751 andDAMA-colchicine (wire models) along with ABI-12cb/tubulin complex inFIG. 32A is displayed. For clarity, only the related secondarystructures forming the binding pocket in β-tubulin are shown in FIG.32A. The overall structures of 12cb, ABT-751 and DAMA-colchicineoverlapped very well in the binding pocket. Several potential hydrogenbonding interactions between compound 12cb and tubulin were identified.The carbonyl group in 12cb was in sufficient proximity to form twohydrogen bond interactions with the backbone NH of Leu-252 in H8 and thesidechain of Asp-251 in T7 of the tubulin β-monomer. The para-fluorinesubstituent in the C-ring was close to the sidechain of Cys241 in T7 andTyr202 in S6, possibly forming one or two hydrogen bonds. The imidazoleproton is very close and likely to form a hydrogen bond to Thr179 in T5loop (residues 173-182) of the tubulin α-monomer (FIG. 32A). Togetherwith the hydrophobic interactions provided by the aromatic rings, thelikely formation of these hydrogen bonds would contribute to the highbinding affinity to the tubulin dimer, resulting in highantiproliferative potency.

The binding mode of 11cb will be conceivably less defined since two ofthe three aromatic rings may occupy the binding pocket in the β-monomerwhile the third ring may extend toward the interface of theα/β-monomers, similar to how the sidechain of DAMA-colchicine binds. Ourmodeling indicates that the protecting group likely extends to thetubulin dimer interface, while the A, C rings of 11cb occupy similarbinding pocket and orientation as 12cb (FIG. 32B). This may explain thesimilar activity between the two compounds, even though 11cb has anextra ring system. From the molecular modeling studies presented inFIGS. 32A and 32B, the hydrogen bond donor is likely to be the thiolgroup in Cys-241 in loop 7 of the β-subunit in α/β-tubulin dimer.

The binding mode of ABI 12fb was modeled (not shown) and compared toDAMA-colchicine (see FIG. 19 for structure of colchicine) in theα/β-tubulin heterodimer. The overall structure of 12fb andDAMA-cochicine overlapped very well. The p-fluoro phenyl moiety overlapswith the trimethoxylpheny moiety which is interacting with the T7 loopin the β-subunit. Similarly, the p-chloro phenyl moiety occupies theother side of the pocket where the seven-member ring of theDAMA-cochicine is, with the chlorine atom occupying the pocket where themethoxy moiety interacts.

Example 24 Microtobule Imaging Materials and Methods

Cellomics Cytoskeleton rearrangement kit (Thermo Scientific, Rockford,Ill.) was used to get a visually appreciable proof of ABIs interactingwith tubulin inside the cells. WM-164 melanoma cells were treated witheach compound for 18 h in duplicate using a collagen-coated 96-wellplate (Becton Dickinson Labware, Bedford, Mass.). Then cells were fixedwith 4% paraformaldehyde (Thermo Scientific, Rockford, Ill.) andpermeabilized using permeabilization buffer supply from the kit. Primaryantibody for tubulin and fluorescence-labeled secondary antibody weresubsequently added to the cells. Cell nuclei were stained by DAPI. WholeCell Stain Green was also applied to all cells. All images were acquiredwith an Olympus IX71 inverted fluorescence microscope (Olympus Corp.,Tokyo, Japan) with overlays from separate images of tubulin (red),nuclei (blue), and whole cells (green). For comparison, paclitaxel,colchicine and ABT-751, along with ABIs are included.

Results

Visual proof of ABIs interacting with tubulin inside the cells wasexamined. The mictotubule arrangement in human melanoma WM-164 cellsupon treatment with different compounds is presented in FIG. 33. Themicrotubule images clearly showed that all five tested compoundsresulted in cytoskeleton rearrangement. There was a significantdifference between paclitaxel and the other four compounds (colchicine,ABT-751, 12cb, and 12da). Treatment with paclitaxel resulted in acondensation of microtubules orderly lying around the nuclei comparedwith controls, consistent with its mechanisms of action for stabilizingmicrotubules. On the contrary, treatment with colchicine, ABT-751, 12cb,and 12da had similar effects on microtubules and resulted in some degreeof microtubule fragmentation, consistent with their common mechanism ofaction for destabilizing microtubules. These results also confirmed thatABIs shared the same cellular target with colchicine and induced thesame cellular effect.

Example 25 Vascular Disrupting Activity of Compounds 17ya and 55 Method

Cells.

HUVECs (Human Umbilical Vein Endothelial Cells) were cultured and grownin EGM-2 BulletKit (Lonza, Cat No. CC-3162), which contains growthsupplements including hydrocortisone, human fibroblast growthfactor-basic with heparin (hFGF-B), vascular endothelial growth factor(VEGF), R3-insulin-like growth factor 1 (IGF-1), ascorbic acid, heparin,fetal bovine serum, human epidermal growth factor (hEGF), and GA-1000(gentamicin and amphotericin B) in Endothelial Cell Basal Medium-2.Cells between the third and fifth passages were used for experiments.PC-3 human prostate cancer cells and T47D human breast cancer cells werecultured in RPMI-1640 medium with 5% fetal bovine serum.

Cell Growth Inhibition Studies.

Cytotoxic or antiproliferative activity of test compounds wasinvestigated in several cell lines using the sulforhodamine B (SRB)assay. Cultured cells were plated into 96-well plates and incubated inmedium containing different concentrations of the test compounds for 24h or 48 h. Cells were stained with sulphorhodamine B (SRB) solution. Theoptical density was determined at 540 nm on a microplate reader (DynexTechnologies, Chantilly, Va.). Plots of percent inhibition of cellgrowth versus drug concentration were constructed, and the concentrationthat inhibited cell growth by 50% relative to the vehicle control (IC₅₀)was determined by nonlinear least squares regression using WinNonlinsoftware (Pharsight Corporation, Cary, N.C.).

Capillary Formation and Disruption Assays.

Capillary formation assays were performed in 96-well plates by plating12,000 cells/well of HUVECs on a Matrigel layer (BD Biosciences). Inorder to evaluate the anti-capillary action, capillaries were allowed toform over a 16 h period before the addition of test compound orvehicle-control. In addition, capillary formation inhibitory effect oftest compound was investigated by treating HUVEC cells with testcompounds before capillary formation. Images were acquired immediatelyfollowing compound addition, 5, 10, 15, and 25 h after exposure to testcompound. Capillary formation was quantified by counting the number oftubes and nodes having at least three edges.

Endothelial Monolayer Permeability Assay.

The permeability of an endothelial cell monolayer was assessed in thetranswell system. HUVECs were plated at 2×10⁶ cells per insert of 24well plate in EGM-2 medium and incubated for 72 h to reach 100%confluency. Test compounds were diluted in EGM-2 medium and added to theupper chamber of the apparatus. Following 1, 2, and 4 h of incubation,the compounds were removed and 75 μg/mL FITC-conjugated dextran (MW40,000) was added for 5 minutes. Fluorescent measurements of the lowerchamber were taken after excitation at 485 nm and emission was measuredat 520 nm using a BioTek Synergy 4 Microplate Reader.

Result

17Ya and 55 Exhibited High Antiproliferative Activity AgainstEndothelial Cells.

17ya and 55 were evaluated for cytotoxic activity against growthfactor-supplemented endothelial cells and growth factor-deprivedendothelial cell cultures. Combretastatin A-4 (CA4) and doxorubicin wereused as positive and negative control, respectively. Compound 17yaexhibited higher potency than compound 55 against actively proliferatingendothelial cells (Table 24 and FIG. 35). Both 17ya and 55 exhibitedselectivity for endothelial cells showing lower IC₅₀ values compared toone of the prostate cancer cells. CA4, 17ya and 55 were 8, 5 and 3 timesmore active against endothelial cells than against cancer cells,respectively, while doxorubicin was not specific to endothelial cells(Table 24 and FIG. 35). However no selectivity was observed betweenquiescent and active endothelial cells with these compounds (data notshown).

TABLE 24 Endothelial cell growth inhibition of 17ya and 55. N = 3 CA4Doxorubicin 17ya 55

PC3 3.2 397.0  7.8 23.3 T47D 6.0 352.8 18.0 37.4 HUVEC 1.2 273.6  2.8 9.7 Selectivity 7.6  1.4  4.6  3.1 ratio*, cancer cells/ HUVEC *Toobtain the selectivity ratio between cancer cells and HUVEC cells, themean IC₅₀ (nM) values of test compounds in PC3 and T47D cells were used.

17ya Disrupts the Formation of Endothelial Capillaries but does notDisrupt Preformed Capillaries.

The activity of 17ya was investigated on endothelial cells engaged incapillary tube formation in vitro. Endothelial cells were placed on aMatrigel matrix and the formation and construction of capillary tubes inthe presence or absence of compounds were observed (CA4, doxorubicin,and 17ya).

To avoid confusion between early stage of tube formation and disruptionof tube construction, HUVEC cells on matrix in the presence of drugtreatment were incubated for 15 h. Then disruption of capillary wasdetermined by counting the number of tubes and nodes in each treatmentgroup. On the other hand, to evaluate the effect of test compound inpreformed capillaries, HUVEC cells on matrix were allowed to formcapillary tube for 16 h and the capillaries were treated with testcompounds.

As a result, the number of tubes and nodes was gradually decreased overtime due to deficiency or consumption of nutrient by HUVEC cells (FIG.36). This trend was observed in every drug treatment group (FIG. 36). Inorder to examine the difference between untreated and pretreatedcapillaries 15 h incubation groups were compared (FIG. 36).

Endothelial cells that were exposed to various concentrations of 17ya (0to 50 μM) plated on Matrigel matrix resulted in inhibition of tubeformation in a dose dependent manner. 17ya with approximate IC₅₀ valueof 5 nM in cell growth inhibition studies inhibited more than 50% oftube formation compared to vehicle-control (FIG. 37). 17ya at 10 nMcompletely inhibited the tube formation (FIG. 37). However, in thepreformed capillaries, the 10 nM 17ya treatment group did not disruptthe capillary structure by 15 h (FIG. 36). These results suggest that17ya inhibits the formation of endothelial capillaries significantly butis less effective to disrupt preformed capillaries. Similar result wasobserved in CA4 treatment group (FIG. 37). However, doxorubicin did notaffect the capillary construction at toxic concentration.

17ya and 55 Increased the Permeability of Endothelial Cell Monolayers.

Antitubulin agents could modify the integrity of endothelial cell layerslining blood vessels by targeting cytoskeleton of the endothelial cells.Thus, the vascular disruption effect of antitubulin agent is known toincrease the permeability of blood vessel and thus could lead to proteinleakage and high blood viscosity. This could result in reduction ofblood flow, causing subsequent tumor death from hypoxia and nutrientdeprivation.

The effect of 17ya and 55 was evaluated on vascular permeability usingin vitro study using transwell system with confluent HUVEC monolayers.The change in permeability by test compound was measured by the leakageof dextran (MW 40,000) after 1, 2, and 4 h of drug treatment. CA4 wasused as a positive control. CA4, 17ya, and 55 resulted in increasedpermeability and the effect was more pronounced at 1 h incubation (datawas not shown). 17ya showed a potency similar to CA4 (FIG. 38).Doxorubicin did not induce any change in the permeability of endothelialcell monolayer (FIG. 38).

Example 26 Synthesis of(Benzofuranyl-1H-Imidazol-4-yl)(3,4,5-Trimethoxyphenyl)Methanone(17ya(i)) and(Benzothiophenyl-1H-Imidazol-4-yl)(3,4,5-Trimethoxyphenyl)Methanones(17ya(ii))

Synthesis of(2-(Benzofuran-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya(i)), and(2-(benzo[b]thiophen-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone(17ya(ii))

To a solution of compounds 10y (i, ii) (2.32 g, 5.0 mmol) in anhydrousTHF (100 ml) at −78° C. was added 1.7 M tert-butyllithium in pentane(3.5 mL, 6.0 mmol) and stirred for 10 min. A solution of3,4,5-trimethoxybenzoyl chloride (1.38 g, 6.0 mmol) in THF was added at−78° C. and stirred overnight. The reaction mixture was quenched with100 ml of saturated NaHCO₃ solution (aqueous) and extracted by ethylacetate (300 ml). The organic layer was dried over magnesium sulfate andconcentrated. The residue was used for next step by adding 10 mL of 1.0M tetrabutyl ammonium fluoride and stirred overnight. The reactionmixture was diluted by 200 ml of saturated NaHCO₃ solution (aqueous) andextracted by ethyl acetate (200 ml). The organic layer was dried overmagnesium sulfate and concentrated. The residue was purified by flashcolumn chromatography (hexane:ethyl acetate 3:1) to give a white solid.17ya (i): 4.7% yield. Mp 208-210° C. ¹H NMR (CDCl₃, 500 MHz) δ 8.77 (s,1H), 8.12 (d, J=7.6 Hz, 1H), 7.90 (s, 1H), 7.632-7.65 (m, 1H), 7.44-7.49(m, 2H), 7.29 (s, 2H), 3.99 (s, 3H), 3.93 (s, 6H). MS (ESI) calcd forC₂₁H₁₈N₂O₅ 378.1, found 377.1[M−H]⁻. HPLC1: t_(R) 5.18 min, purity98.8%. 17ya(ii): 3.2% yield. Mp 185-187° C. ¹H NMR (CDCl₃, 500 MHz) δ10.62 (s, 1H), 8.74 (d, J=5.0 Hz, 1H), 8.06 (s, 1H), 7.92-7.95 (m, 2H),7.48-7.54 (m, 2H), 7.29 (s, 2H), 3.99 (s, 3H), 3.97 (s, 6H). MS (ESI)calcd for C₂₁H₁₈N₂O₄S 394.1, found 392.8[M−H]⁻. HPLC: t_(R) 5.38 min,purity 95.6%.

Example 27 Synthesis of Aryl Benzoyl Imidazole General Procedure for thePreparation of (4 or 5)-aryl-2-aryloyl-(1H)-Imidazole Derivatives (FIG.40)

To ammonium acetate (10 mmol) in ethanol (5 mL) and water (0.3 ml) wasadded arylglyoxal hydrate 103 (1 mmol) in ethanol (5 ml) and3,4,5-trimethoxyphenyl glyoxal hydrate 104 (1 mmol) in ethanol (10 ml).The mixture was stirred at room temperature for 30-45 min. The reactionwas stopped after the consumption of the starting material monitored byTLC. The mixture was then extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated to get the crude product. The crude was purified by flashchromatography.

(The two IUPAC names given below correspond to freely interconvertingtautomers, not unresolved mixtures.)

Phenyl-(4-phenyl-1H-imidazol-2-yl)methanone andphenyl-(5-phenyl-1H-imidazol-2-yl)methanone (70aa)

¹H NMR (500 MHz, DMSO-d₆): δ 13.80 (s, 0.25H), 13.63 (s, 1H), 8.60 (d,J=7.76 Hz, 2H), 8.47 (d, J=7.7 Hz, 0.5H), 8.08 (s, 1H), 7.97 (d, J=7.95Hz, 0.5H), 7.94 (d, J=7.64 Hz, 2H), 7.79 (s, 0.25H), 7.69 (t, J=7.1 Hz,1H), 7.66 (t, J=7.6 Hz, 0.25H), 7.60 (t, J=7.6 Hz, 2H), 7.57 (t, J=8.1Hz, 0.5H), 7.47 (t, J=7.55 Hz, 0.5H), 7.42 (t, J=7.7 Hz, 2H), 7.37 (t,J=7.1 Hz, 0.25H), 7.28 (t, J=7.3 Hz, 1H).

(4-Fluorophenyl)(4-(4-fluorophenyl)-1H-imidazol-2-yl)methanone and(4-fluorophenyl)(5-(4-fluorophenyl)-1H-imidazol-2-yl)methanone (70r)

¹H NMR (400 MHz, chloroform-d) δ 10.68 (s, 1H), 10.52 (s, 1H), 8.93-8.82(dd, J=5.89, 8.64 Hz, 2H), 8.72 (dd, J=5.60, 8.70 Hz, 0.39H), 7.89 (dd,J=5.39, 8.72 Hz, 2H), 7.63 (dd, J=5.05, 8.25 Hz, 0.46H), 7.59 (d, J=2.2Hz, 0.29 H), 7.55 (d, J=2.8 Hz, 1H) 7.25-7.20 (m, 2H), 7.20-7.13 (m,2H).

(4-Chlorophenyl)(4-(4-chlorophenyl)-1H-imidazol-2-yl)methanone and(4-chlorophenyl)(5-(4-chlorophenyl)-1H-imidazol-2-yl)methanone (70s)

¹H NMR (400 MHz, chloroform-d) δ 10.70 (s, 0.65 H), 10.55 (s, 1H), 8.78(d, J=8.65 Hz, 2H), 8.63 (s, 1H), 7.87 (s, 2H), 7.66-7.52 (m, 5H),7.50-7.39 (m, 2H).

4-Bromophenyl-(4-(4-bromophenyl)-1H-imidazol-2-yl)ketone and4-bromophenyl-(5-(4-bromophenyl)-1H-imidazol-2-yl)methanone (70t)

¹H NMR (500 MHz, DMSO-d₆) δ 13.91 (s, 0.16H), 13.73 (s, 1H), 8.51 (d,J=8.4 Hz, 2H), 8.42 (d, J=8.3 Hz, 0.32H), 8.16 (s, 1H), 7.93 (d, J=8.15Hz, 0.32H), 7.89 (d, J=8.35 Hz, 2H), 7.83 (d, J=8.45 Hz, 2H), 7.80 (d,J=8.4 Hz, 0.32H), 7.79 (s, 0.16H), 7.67 (d, J=8.05 Hz, 0.32H), 7.62 (d,J=8.35 Hz, 2H).

p-Tolyl(4-p-tolyl-1H-imidazol-2-yl)methanone andp-tolyl(5-p-tolyl-1H-imidazol-2-yl)methanone (70v)

¹H NMR (400 MHz, chloroform-d) δ 10.96 (s, 1H), 10.73 (s, 1H), 8.71 (d,J=8.26 Hz, 2H), 8.54 (d, J=8.23 Hz, 2H), 7.82 (d, J=8.11 Hz, 2H),7.67-7.49 (m, 4H), 7.37 (t, J=7.62, 7.62 Hz, 4H), 7.30 (s, 1H), 7.28 (s,2H), 7.26 (s, 1H), 2.49 (d, J=4.52 Hz, 6H), 2.42 (d, J=4.95 Hz, 6H).

(4-(Trifluoromethyl)phenyl)(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)methanoneand(4-(trifluoromethyl)phenyl)(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)methanone(70u)

¹H NMR (400 MHz, chloroform-d) δ 10.83 (s, 0.38H), 10.60 (s, 1H), 8.78(d, J=8.19 Hz, 2H), 8.64 (d, J=8.13 Hz, 0.48H), 7.93 (d, J=8.34 Hz, 2H),7.76 (d, J=8.56 Hz, 2H), 7.66-7.59 (m, 3H).

(4-Methoxyphenyl)(4-(4-methoxyphenyl)-1H-imidazol-2-yl)methanone and(4-methoxyphenyl)(5-(4-methoxyphenyl)-1H-imidazol-2-yl)methanone (70w)

¹H NMR (400 MHz, chloroform-d) δ 10.50 (s, 1H), 10.38 (s, 1H), 8.77 (d,J=8.90 Hz, 2H), 8.60 (d, J=8.89 Hz, 2H), 7.77 (s, 1H), 7.75 (s, 1H),7.48 (d, J=8.75 Hz, 1H), 7.45-7.36 (m, 2H), 7.03-6.87 (m, 5H), 3.86 (s,2H), 3.85 (s, 2H), 3.84 (s, 2H), 3.80 (s, 2H), 3.79 (s, 2H).

(4-(Dimethylamino)phenyl)(4-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)methanoneand(4-(dimethylamino)phenyl)(5-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)methanone(70hh)

¹H NMR (500 MHz, DMSO-d₆) δ 13.17 (s, 0.35H), 13.12 (s, 1H), 8.64 (d,J=8.95 Hz, 2H), 8.50 (d, J=8.95 Hz, 1H), 7.80-7.69 (m, 4H), 7.50 (s,1H), 6.82 (d, J=8.99 Hz, 2H), 6.76 (t, J=7.70, 7.70 Hz, 5H), 3.07 (s,6H), 3.05 (s, 4H), 2.95 (s, 4H), 2.93 (s, 6H).

(4-Hydroxyphenyl)(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)methanone and(4-hydroxyphenyl)(5-(4-hydroxyphenyl)-1H-imidazol-2-yl)methanone (70ii)

¹H NMR (500 MHz, DMSO-d₆) δ 13.37 (s, 0.37H), 13.29 (s, 1H), 10.39 (s,1H), 9.46 (s, 1H), 8.60 (d, J=7.88 Hz, 3H), 8.47 (s, 1H), 7.79 (s, 2H),7.73 (d, J=7.48 Hz, 4H), 7.55 (s, 1H), 6.92 (d, J=8.02 Hz, 4H), 6.81 (d,J=8.03 Hz, 4H).

(4-Phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone and(5-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone (70a)

¹H NMR (400 MHz, chloroform-d) δ 10.63 (s, 0.48H), 10.47 (s, 1H), 8.19(s, 2H), 7.98 (s, 1H), 7.82 (t, J=1.67, 1.67 Hz, 1H), 7.81 (t, J=1.11,1.11 Hz, 1H), 7.60-7.53 (m, 1H), 7.51 (d, J=1.97 Hz, 1H), 7.46-7.30 (m,3H), 7.29-7.22 (m, 1H), 3.95 (s, 5H), 3.91 (s, 3H), 3.91 (s, 3H), 3.89(s, 1H).

(4-(4-Fluorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-fluorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70b)

¹H NMR (400 MHz, chloroform-d) δ 10.60 (s, 0.30H), 10.46 (s, 1H), 8.15(s, 2H), 7.97 (s, 1H), 7.77 (dd, J=5.35, 8.90 Hz, 2H), 7.58-7.50 (dd,J=5.10, 8.20 Hz, 0.47 H), 7.48 (s, 0.46 H), 7.46 (s, 1H), 7.45 (s, 1H),7.10-7.02 (m, 2H), 3.94 (s, 6H), 3.92 (s, 3H), 3.91 (s, 2H), 3.89 (s,1H).

(4-(4-Chlorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-chlorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70c)

¹H NMR (400 MHz, chloroform-d) δ 10.57 (s, 0.33H), 10.45 (s, 1H), 8.15(s, 2H), 7.97 (s, 0.49H), 7.81-7.68 (m, 2H), 7.51-7.47 (m, 1H),7.36-7.30 (m, 2H), 3.94 (s, 6H), 3.91 (s, 3H), 3.89 (s, 0.75H).

(4-(4-Bromophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-bromophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70d)

¹H NMR (400 MHz, chloroform-d) δ 10.77 (s, 0.36H), 10.59 (s, 1H), 8.24(s, 2H), 8.06 (s, 1H), 7.78 (d, J=1.86 Hz, 1H), 7.76 (d, J=1.98 Hz, 1H),7.69-7.47 (m, 4H), 4.03 (s, 6H), 4.01 (s, 3H), 4.00 (s, 2H), 3.99 (s,1H).

(4-p-Tolyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone and(5-p-tolyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone (70f)

¹H NMR (400 MHz, chloroform-d) δ 10.57 (s, 0.77H), 10.44 (s, 1H), 8.18(s, 2H), 7.96 (s, 1H), 7.71 (d, J=1.87 Hz, 1H), 7.69 (d, J=1.88 Hz, 1H),7.47 (d, J=2.44 Hz, 2H), 7.22 (s, 1H), 7.16 (s, 1H), 3.94 (s, 6H), 3.92(s, 3H), 3.90 (s, 3H), 3.89 (s, 2H).

(4-(4-(Trifluoromethyl)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70e)

¹H NMR (400 MHz, chloroform-d) δ 10.90 (s, 0.16H), 10.67 (s, 1H), 8.26(s, 2H), 8.08 (s, 0.36H), 8.01 (d, J=7.30 Hz, 2H), 7.80-7.88 (m, 0.79H),7.76-7.62 (m, 3H), 4.08-3.95 (m, 11H).

(4-(4-Methoxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-methoxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70g)

¹H NMR (400 MHz, chloroform-d) δ 10.60 (s, 1H), 10.50 (s, 1H), 8.27 (s,2H), 8.05 (s, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.59 (d, J=8.87 Hz, 1H),7.54 (d, J=1.90 Hz, 1H), 7.51 (d, J=2.31 Hz, 1H), 7.05-6.97 (m, 4H),4.04 (s, 5H), 4.01 (s, 3H), 4.00 (s, 3H), 3.98 (s, 2H), 3.89 (s, 2H),3.88 (s, 3H).

(4-(4-(Dimethylamino)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70h)

¹H NMR (500 MHz, chloroform-d) δ 10.67 (s, 1H), 10.54 (s, 0.49H), 8.28(s, 1H), 8.03 (s, 2H), 7.78 (s, 1H), 7.76 (s, 1H), 7.53 (d, J=8.79 Hz,2H), 7.50 (d, J=1.56 Hz, 1H), 6.78 (m, 4H), 4.03 (s, 4H), 3.99 (s, 8H),3.97 (s, 3H), 3.04 (s, 6H), 3.02 (s, 4H).

(4-(4-Hydroxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-(4-hydroxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone)(70i)

¹H NMR (500 MHz, chloroform-d) δ 11.19 (s, 1H), 10.75 (s, 1H), 8.23 (s,2H), 7.98 (s, 2H), 7.77 (s, 1H), 7.75 (s, 1H), 7.54 (d, J=5.13 Hz, 3H),7.49 (s, 1H), 6.90 (t, J=9.24, 9.24 Hz, 4H), 4.01 (s, 6H), 3.99 (s, 3H),3.97 (s, 5H), 3.96 (s, 3H).

Phenyl(4-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone andphenyl(5-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone (70x)

¹H NMR (400 MHz, chloroform-d) δ 10.67 (s, 0.69H), 10.51 (s, 1H),8.74-8.61 (m, 2H), 8.56-8.43 (m, 1H), 7.63-7.54 (m, 1H), 7.53-7.43 (m,4H), 7.04 (s, 2H), 6.75 (s, 1H), 3.89 (s, 6H), 3.89 (s, 3H), 3.83 (s,1H), 3.82 (s, 2H).

4-Methoxyphenyl(4-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanoneand4-methoxyphenyl(5-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone(70y)

¹H NMR (400 MHz, chloroform-d) δ 10.79 (s, 1H), 10.66 (s, 1H), 8.83 (d,J=8.96 Hz, 2H), 8.70 (d, J=8.92 Hz, 1H), 7.56 (d, J=1.72 Hz, 1H), 7.53(d, J=2.25 Hz, 1H), 7.14 (s, 2H), 7.06 (d, J=3.68 Hz, 1H), 7.04 (d,J=3.51 Hz, 1H), 6.83 (s, 1H), 3.99 (s, 5H), 3.96 (s, 4H), 3.95 (s, 3H),3.94 (s, 2H), 3.92 (s, 2H), 3.91 (s, 2H).

4-Bromophenyl(4-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone and4-bromophenyl(5-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone(70z)

¹H NMR (400 MHz, chloroform-d) δ 10.66 (s, 0.54H), 10.57 (s, 1H),8.68-8.63 (m, 2H), 8.56-8.51 (m, 1H), 7.80-7.75 (m, 1H), 7.73-7.69 (m,2H), 7.61-7.55 (m, 2H), 7.12 (s, 2H), 6.82 (s, 1H), 4.02 (s, 3H), 3.98(s, 6H), 3.93 (s, 1H), 3.92 (s, 2H).

3,4,5-Trimethoxyphenyl-(4-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanoneand3,4,5-trimethoxyphenyl-(5-(3,4,5-trimethoxyphenyl)-1H-imidazol-2-yl)methanone(70q)

¹H NMR (400 MHz, chloroform-d) δ 10.76 (s, 0.40H), 10.61 (s, 1H), 8.20(s, 2H), 7.95 (s, 1H), 7.48 (d, J=1.90 Hz, 0.40H), 7.47 (d, J=2.34 Hz,1H), 7.06 (s, 2H), 6.75 (s, 1H), 3.93 (s, 5H), 3.91 (d, J=0.84 Hz, 4H),3.89 (s, 1H), 3.87 (s, 2H), 3.86 (s, 5H) 3.83 (s, 1H), 3.82 (s, 2H).

Example 28 Synthesis of Aryl Benzoyl Imidazole General Procedure for thePreparation of (4 or 5)-aryl-2-aryloyl-(1H)-Imidazole Derivatives 70m,70n and 70o

To a solution of 70a (135 mg, 0.4 mmol) in THF (10 mL) in ice-bath wasadded sodium hydride (60% dispersion in mineral oil, 28 mg, 0.60 mmol)followed by adding methyl iodide (85 mg, 0.60 mmol) (for 70m) or ethyliodide (93 mg, 0.60 mmol) (for 70n) or benzyl bromide (102 mg, 0.60mmol) (for 70o). The resulting reaction mixture was stirred overnightunder reflux condition. After dilution by 50 ml of saturated NaHCO₃solution (aqueous), the reaction mixture was extracted by ethyl acetate(100 ml). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography.

(1-Methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70m)

¹H NMR (500 MHz, chloroform-d) δ 7.97 (d, J=2.38 Hz, 2H), 7.85 (d,J=6.01 Hz, 2H), 7.46-7.39 (m, 3H), 7.28 (d, J=2.39 Hz, 1H), 4.16-4.10(m, 3H), 3.99 (d, J=2.82 Hz, 9H).

(1-Ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70n)

¹H NMR (400 MHz, chloroform-d) δ 7.95 (s, 2H), 7.89-7.83 (m, 2H), 7.51(s, 1H), 7.43 (t, J=7.61, 7.61 Hz, 2H), 7.36-7.31 (m, 1H), 4.56 (q,J=7.19, 7.19, 7.19 Hz, 2H), 3.99 (s, 6H), 3.98 (s, 3H), 1.30 (t, J=7.19,7.19 Hz, 3H).

(1-Benzyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70o)

¹H NMR (500 MHz, chloroform-d) δ 7.94 (d, J=1.70 Hz, 2H), 7.84 (d,J=7.73 Hz, 2H), 7.47-7.28 (m, 9H), 5.74 (s, 2H), 3.98 (s, 9H).

Synthesis of Compound 105

To a solution of 70a (135 mg, 0.4 mmol) in THF (10 mL) in ice-bath wasadded sodium hydride (60% dispersion in mineral oil, 28 mg, 0.60 mmol)followed by adding excessive methyl iodide. The resulting reactionmixture was stirred overnight under reflux condition. After dilution by50 ml of saturated NaHCO₃ solution (aqueous), the reaction mixture wasextracted by ethyl acetate (100 ml). The organic layer was dried overmagnesium sulfate and concentrated. The residue was purified by flashcolumn chromatography.

(1,3-Dimethyl-4-phenyl-2,3-dihydro-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(105)

¹H NMR (400 MHz, chloroform-d) δ 7.78-7.62 (m, 2H), 7.39-7.25 (m, 3H),7.06 (s, 1H), 6.55 (d, J=0.78 Hz, 2H), 5.55 (s, 1H), 3.75 (d, J=9.74 Hz,9H), 3.41 (d, J=1.10 Hz, 6H).

In vitro growth inhibitory effects (IC₅₀ (nM)) of compound 105 of LNCaPis 4235 nM; of PC3 is 3487 nM and of PPC1 is 5294 nM.

Example 29 Synthesis of Aryl Benzoyl Imidazole General Procedure for thePreparation of (4 or 5)-alkyl-(5 or 4)-aryl-2-aryloyl-(1H)-ImidazoleDerivatives (70j, 70k, 70l) (FIG. 41)

To ammonium acetate (10 mmol) in ethanol (5 ml) and water (0.3 ml) wasadded phenyl alkyl diones 101 (b-d) (1 mmol) in ethanol (5 ml) and3,4,5-trimethoxyphenyl glyoxal hydrate 104 (1 mmol) in ethanol (10 ml).The mixture was stirred at room temperature for 30-45 min. The reactionwas stopped after the consumption of the starting material monitored byTLC. The mixture was then extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated to get the crude product. The crude was purified by flashchromatography.

(5-Methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(4-methyl-5-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70j)

¹H NMR (400 MHz, chloroform-d) δ 10.43 (s, 0.59H), 10.32 (s, 1H), 8.24(s, 2H), 8.05 (s, 1H), 7.87-7.71 (m, 3H), 7.62-7.38 (m, 6H), 4.02 (s,5H), 4.01 (s, 3H), 3.99 (s, 2H), 3.98 (s, 2H), 3.95 (s, 2H), 2.64 (s,3H), 2.56 (s, 1H).

(5-Ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone and(4-ethyl-5-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70k)

¹H NMR (400 MHz, chloroform-d) δ 10.85 (s, 1H), 8.28 (s, 2H), 8.15 (s,1H), 7.75 (m, 1H), 7.45-7.30 (m, 5H), 4.00 (m, 9H), 3.05 (m, 2H), 1.40(m, 3H).

(4-Phenyl-5-propyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanoneand(5-phenyl-4-propyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70l)

¹H NMR (400 MHz, chloroform-d) δ 10.52 (s, 0.52 H), 10.47 (s, 1H), 8.24(s, 2H), 8.14 (s, 1H), 7.78 (d, J=7.39 Hz, 2H), 7.60-7.43 (m, 5H), 7.36(t, J=7.40, 7.40 Hz, 1H), 4.01 (s, 5H), 4.00 (s, 3H), 3.99 (s, 4H),3.00-2.93 (t, J=7.40, 7.40 Hz, 2H), 2.84 (t, J=7.50, 7.50 Hz, 1H),1.94-1.87 (m, 1H), 1.87-1.78 (m, 2H), 1.07 (t, J=7.33, 7.33 Hz, 3H),0.98-0.92 (t, J=7.10, 7.10 Hz, 1H).

Synthesis of Compound 70p

To a solution of 70a (135 mg, 0.4 mmol) in ACN (10 mL) was addedpotassium carbonate (82 mg, 0.60 mmol) followed by cyclopentyl bromide(72 mg, 0.48 mmol). The resulting reaction mixture was stirred overnightunder reflux condition. After dilution by 50 ml of saturated NaHCO₃solution (aqueous), the reaction mixture was extracted by ethyl acetate(100 ml). The organic layer was dried over magnesium sulfate andconcentrated. The residue was purified by flash column chromatography.

(1-cyclopentyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70p)

¹H NMR (500 MHz, chloroform-d) δ 7.90-7.82 (m, 4H), 7.61 (d, J=1.7 Hz,1H), 7.42 (td, J=7.7, 1.7 Hz, 2H), 7.33-7.28 (m, 1H), 5.88-5.32 (m, 1H),3.98 (t, J=1.9 Hz, 9H), 2.64-2.20 (m, 2H), 2.00-1.77 (m, 6H).

Synthesis of Compound 70ab

To a solution of 70a (135 mg, 0.4 mmol) in ACN (10 mL) was addedpotassium carbonate (82 mg, 0.60 mmol) followed by n-propyl iodide (82mg, 0.48 mmol). The resulting reaction mixture was stirred overnightunder reflux condition. After dilution by 50 ml of saturated NaHCO₃solution (aqueous), the reaction mixture was extracted by ethyl acetate(100 ml). The organic layer was dried over sodium sulfate andconcentrated. The residue was purified by flash column chromatography.

Synthesis of Compound 70ac

To a solution of 70a (135 mg, 0.4 mmol) in ACN (10 mL) was addedpotassium carbonate (82 mg, 0.60 mmol) followed by isopropyl iodide (82mg, 0.48 mmol). The resulting reaction mixture was stirred overnightunder reflux condition. After dilution by 50 ml of saturated NaHCO₃solution (aqueous), the reaction mixture was extracted by ethyl acetate(100 ml). The organic layer was dried over sodium sulfate andconcentrated. The residue was purified by flash column chromatography.

Synthesis of Compound 70ad

Under inert atmosphere, a Schlenk flask was charged with Cs₂CO₃ (260 mg,0.8 mmol), CuI (76 mg, 0.4 mmol), ligand (0.4 mmol), compound 70a (135mg, 0.4 mmol), 2-pyrimidyl bromide (124 mg, 0.8 mmol), and DMF (5 mL).The reaction mixture was stirred for 30 min at room temperature, andthen heated to 110° C. for 2 days. The reaction mixture was monitored byTLC. After the starting material was completely consumed, the reactionwas stopped and the mixture was cooled to room temperature. The reactionmixture was directly passed through a plug of silca gel. After beingrinsed with ethyl acetate, the combined filtrate was washed withsaturated brine. After the organic layer was dried by sodium sulfate, itwas concentrated. The residue was purified by column chromatography onsilica gel to provide the desired product.

Example 30 Synthesis of Aryl Benzyl Imidazole

General Procedure for the Synthesis of 5-(alkyl oraryl)-4-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole and 4-(alkyl oraryl)-5-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102 (a-e)

To a solution of the aldehyde 100 (5 mmol) in ethanol (20 mL) at 0° C.was added the phenyl alkyl dione 101 (5.5 mmol) and a solution of 29%ammonium hydroxide in water (50 mmol, 7 mL). After stifling for 2-3 daysat room temperature, the reaction mixture was concentrated and theresidue was subjected to flash column chromatography withdichloromethane as eluent to yield the titled compound as a yellowpowder. Yield: 20-30%.

5-Phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole and4-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102a)

¹H NMR (500 MHz, chloroform-d) δ 7.91-7.62 (m, 2H), 7.43-7.34 (m, 2H),7.27-7.21 (m, 2H), 6.51 (s, 2H), 4.12 (s, 2H), 3.86 (s, 3H), 3.84 (s,6H).

5-Methyl-4-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole and4-methyl-5-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102b)

¹H NMR (500 MHz, chloroform-d) δ 7.55 (d, J=7.6 Hz, 2H), 7.43-7.37 (m,2H), 7.25 (d, J=6.7 Hz, 1H), 6.49 (s, 2H), 4.03 (s, 2H), 3.84 (d, J=1.3Hz, 3H), 3.81 (d, J=1.2 Hz, 6H), 2.42 (s, 3H).

5-Ethyl-4-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole and4-ethyl-5-phenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102c)

¹H NMR (500 MHz, chloroform-d) δ 8.47 (s, 0.42H), 8.39 (s, 0.58H),7.86-7.62 (m, 2H), 7.41 (m, 2H), 7.35-7.31 (m, 1H), 6.54 (m, 2H), 4.10(m, 2H), 3.90-3.83 (m, 9H), 2.79 (m, 2H), 1.38-1.17 (m, 3H).

4-Phenyl-5-propyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole and5-phenyl-4-propyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102d)

¹H NMR (400 MHz, chloroform-d) δ 8.63 (s, 0.48H), 8.50 (s, 0.52H),7.70-7.64 (m, 1H), 7.41 (m, 3H), 7.37-7.32 (m, 1H), 6.52 (d, J=1.3 Hz,2H), 4.08 (d, J=5.1 Hz, 2H), 3.87 (m, 3H), 3.86-3.84 (m, 6H), 2.73 (m,2H), 1.88-1.75 (m, 1H), 1.64 (m, 1H), 0.98 (m, 3H).

4,5-Diphenyl-2-(3,4,5-trimethoxybenzyl)-1H-imidazole (102e)

¹H NMR (400 MHz, chloroform-d) δ 7.44-7.36 (m, 4H), 7.28-7.20 (m, 6H),6.50 (s, 2H), 4.08 (s, 2H), 3.78 (m, 9H).

Example 31 In Vivo Efficacy in Leukemia (HL60) Xenograft (FIG. 42)

HL60 cells (10×10⁷ per mL) were prepared in RPMI1640 growth mediacontaining 10% FBS, and mixed with Matrigel (BD Biosciences, San Jose,Calif.) at 1:1 ratio. Tumors were established by injecting 100 μL of themixture (5×10⁶ cells per animal) subcutaneously into the flank of6-8-week-old male athymic nude mice. Length and width of tumors weremeasured and the tumor volume (mm³) was calculated by the formula,π/6×L×W², where length (L) and width (W) were determined in mm. When thetumor volumes reached 200 mm³ approximately, the animals bearing HL60tumors were treated with vehicle [Tween80/DMSO/H₂O (2/2/6)], or 17ya (20mg/kg) orally. The dosing schedule was once a week for two weeks.Vincristine (1 mg/mL) was administrated via intraperitoneal injectiononce a week.

Results

Human promyelocytic leukemia cells, HL60 cells were inoculated in nudemice and the tumor volumes were allowed to reach about 200 mm³.Vincristine (1 mg/kg), which is in clinic for hematological cancersincluding leukemia, was used to evaluate the response of this in vivomodel against a positive control drug. The tumor volumes (mm³) wereplotted against time and are the means±SD from four to five animals.HL60 tumor was found to be fast-growing and the volume reached 2000-3000mm³ within two weeks. Though 1 mg/kg intraperitoneal injection ofvincristine exhibited very potent tumor growth inhibitory effect (FIG.42) and the tumor growth inhibition (TGI) was 84%. Orally administered17ya (20 mg/kg) showed 40% tumor growth inhibition. The size of HL60tumors was maintained up to 5 days after 17ya treatment without dramaticincrease but during the next 2 days tumor sizes increased significantly(60-100%). It suggests that more a frequent dosing schedule couldenhance the tumor growth inhibitory effect of 17ya.

All of the features described herein (including any accompanying claims,abstract and drawings), and/or all of the steps of any method or processso disclosed, may be combined with any of the above aspects in anycombination, except combinations where at least some of such featuresand/or steps are mutually exclusive. Although preferred embodiments havebeen depicted and described in detail herein, it will be apparent tothose skilled in the relevant art that various modifications, additions,substitutions, and the like can be made without departing from thespirit of the invention and these are therefore considered to be withinthe scope of the invention as defined in the claims which follow.

What is claimed:
 1. A compound represented by the structure of formulaXXIII:

wherein R₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; R₉ andR₁₂ are independently hydrogen, linear or branched, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH; wherein substitutionsare independently selected from the group of hydroxyl, an aliphaticstraight- or branched-chain C₁ to C₁₀ hydrocarbon, alkoxy, haloalkoxy,aryloxy, nitro, cyano, alkyl-CN, halo, haloalkyl, dihaloalkyl,trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H, C(O)NH₂,—OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl, alkylamino, mesylamino,dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea,alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C₅ toC₇ cycloalkyl, arylalkyl, and combinations thereof; X is a bond, NH, C₁to C₅ hydrocarbon, O, or S; Y is a bond, —C═O, —C═S, —C═N—NH₂, —C═N—OH,—CH—OH, —C═CH—CN, —C═N—CN, —CH═CH—, C═C(CH₃)₂, —C═N-OMe, —(C═O)—NH,—NH—(C═O), —(C═O)—O, —O—(C═O), —(CH₂)₁₋₅—(C═O), (C═O)—(CH₂)₁₋₅,—(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S; i is an integer between 0-5; n isan integer between 1-3; and m is an integer between 1-3; or itspharmaceutically acceptable salt, hydrate, polymorph, metabolite,tautomer or isomer.
 2. The compound of claim 1, wherein said compound isrepresented by the structure of formula XXIV:

R₁, R₂, R₃, R₄, R₅ and R₆ are independently hydrogen, O-alkyl,O-haloalkyl, F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; R₉ andR₁₂ are independently hydrogen, linear or branched, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH; wherein substitutionsare independently selected from the group of hydroxyl, an aliphaticstraight- or branched-chain C₁ to C₁₀ hydrocarbon, alkoxy, haloalkoxy,aryloxy, nitro, cyano, alkyl-CN, halo, haloalkyl, dihaloalkyl,trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H, C(O)NH₂,—OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl, alkylamino, mesylamino,dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea,alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C₅ toC₇ cycloalkyl, arylalkyl, and combinations thereof; Y is a bond, —C═O,—C═S, —C═N—NH₂, —C═N—OH, —CH—OH, —C═CH—CN, —C═N—CN, —CH═CH—, C═C(CH₃)₂,—C═N-OMe, —(C═O)—NH, —NH—(C═O), —(C═O)—O, —O—(C═O), —(CH₂)₁₋₅—(C═O),(C═O)—(CH₂)₁₋₅, —(SO₂)—NH—, —NH—(SO₂)—, SO₂, SO or S; i is an integerbetween 0-5; n is an integer between 1-3; and m is an integer between1-3; or its pharmaceutically acceptable salt, hydrate, polymorph,metabolite, tautomer or isomer.
 3. The compound of claim 1, wherein saidcompound is represented by the structure of formula XXV:

wherein R₄, R₅ and R₆ are independently hydrogen, O-alkyl, O-haloalkyl,F, Cl, Br, I, haloalkyl, CF₃, CN, —CH₂CN, NH₂, hydroxyl,—(CH₂)_(i)NHCH₃, —(CH₂)_(i)NH₂, —(CH₂)_(i)N(CH₃)₂, —OC(O)CF₃, C₁-C₅linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH₂Ph,—NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH₂ or NO₂; R₉ andR₁₂ are independently hydrogen, linear or branched, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, —CH₂Ph, substituted benzyl,haloalkyl, aminoalkyl, —OCH₂Ph, substituted or unsubstituted SO₂-aryl,substituted or unsubstituted —(C═O)-aryl or OH; wherein substitutionsare independently selected from the group of hydroxyl, an aliphaticstraight- or branched-chain C₁ to C₁₀ hydrocarbon, alkoxy, haloalkoxy,aryloxy, nitro, cyano, alkyl-CN, halo, haloalkyl, dihaloalkyl,trihaloalkyl, COOH, C(O)Ph, C(O)-alkyl, C(O)O-alkyl, C(O)H, C(O)NH₂,—OC(O)CF₃, —OCH₂Ph, amino, aminoalkyl, alkylamino, mesylamino,dialkylamino, arylamino, amido, NHC(O)-alkyl, urea, alkyl-urea,alkylamido (e.g., acetamide), haloalkylamido, arylamido, aryl, and C₅ toC₇ cycloalkyl, arylalkyl, and combinations thereof; i is an integerbetween 0-5; and n is an integer between 1-3; or its pharmaceuticallyacceptable salt, hydrate, polymorph, metabolite, tautomer or isomer. 4.The compound of claim 1, wherein said compound is(4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone (70a);(4-(4-fluorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70b);(4-(4-chlorophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70c);(4-(4-bromophenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70d);(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70e); (4-p-tolyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70f);(4-(4-methoxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70g);(4-(4-(dimethylamino)phenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70h);(4-(4-hydroxyphenyl)-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70i);(5-methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70j);(5-ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70k);(4-phenyl-5-propyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70l);(1-methyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70m);(1-ethyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70n);(1-benzyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70o); or(1-cyclopentyl-4-phenyl-1H-imidazol-2-yl)(3,4,5-trimethoxyphenyl)methanone(70p).
 5. A pharmaceutical composition comprising a compound accordingto claim 1 and a pharmaceutically acceptable carrier.
 6. A method oftreating, suppressing, reducing the severity, reducing the risk,inhibiting cancer comprising administering a compound according to claim1 to a subject having cancer under conditions effective to treat thecancer.
 7. The method of claim 6, wherein said cancer is selected fromthe group consisting of prostate cancer, breast cancer, ovarian cancer,skin cancer, melanoma, lung cancer, colon cancer, leukemia, renalcancer, CNS cancer, and combinations thereof.
 8. The method of claim 7,wherein said cancer is metastatic cancer.
 9. The method of claim 7,wherein said administering is carried out in combination with anothercancer therapy.
 10. A method of treating a drug resistant tumor ortumors comprising administering a compound according to claim 1 to asubject suffering from cancer under conditions effective to treat thedrug resistant tumor or tumors.
 11. The method of claim 10, wherein saidtumor is melanoma cancer tumor.
 12. The method of claim 10, wherein saidtumor is metastatic melanoma tumor.
 13. The method of claim 10, whereinsaid tumor is prostate cancer tumor.
 14. The method of claim 10, whereinsaid tumor is ovarian cancer tumor.
 15. The method according to 10,wherein said administering is carried out in combination with anothercancer therapy.
 16. A method of destroying a cancerous cell comprisingproviding a compound according to claim 1 and contacting the cancerouscell with the compound under conditions effective to kill the cancercell.